Electrical ablation devices and methods

ABSTRACT

A method for delivering energy to tissue having a necrotic threshold may generally comprise inserting an electrode array comprising a plurality of electrodes into the tissue, inserting a central electrode into the tissue, positioning a ground pad proximal to the tissue, applying a first sequence of electrical pulses to the electrode array less than the necrotic threshold to induce thermal heating in the tissue, applying a second sequence of electrical pulses to the central electrode equal to or greater than the necrotic threshold to induce cell necrosis in the tissue by irreversible electroporation, and applying a ground potential to the ground pad. Electrical ablation devices and systems and methods of using the same are also described herein.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part application of U.S.application Ser. No. 13/036,908, filed Feb. 28, 2011, titled “ELECTRICALABLATION DEVICES AND METHODS”, which is incorporated herein by referencein its entirety.

BACKGROUND

Electrical ablation therapy has been used in medicine for the treatmentof undesirable tissue, such as, for example, diseased tissue, cancer,malignant and benign tumors, masses, lesions, and other abnormal tissuegrowths. Apparatuses, systems, and methods for conventional ablationtherapies may include electrical ablation therapies, such as, forexample, high temperature thermal therapies including, focusedultrasound ablation, radiofrequency (RF) ablation, and interstitiallaser coagulation, chemical therapies in which chemical agents areinjected into the undesirable tissue to cause ablation, surgicalexcision, cryotherapy, radiation, photodynamic therapy, Moh'smicrographic surgery, topical treatments with 5-fluorouracil, and laserablation. Conventional electrical ablation therapies may suffer fromsome of the following limitations: cost, length of recovery, andextraordinary pain inflicted on the patient. In particular, one drawbackof conventional electrical ablation therapies may be any permanentdamage to healthy tissue surrounding the undesirable tissue due todetrimental thermal effects resulting from exposing the tissue tothermal energy generated by the electrical ablation device. For example,permanent damage to surrounding healthy tissue may occur when using hightemperature thermal therapies to expose undesirable tissue to electricpotentials sufficient to cause cell necrosis.

Additionally, conventional electrical ablation therapies to treat largemasses of undesirable tissue may comprise treating a first portion ofthe tissue treatment region, repositioning the electrical ablationdevice, and treating the remaining portion of the tissue treatmentregion. Conventional electrical ablation therapies to treat large massesof undesirable tissue may suffer from some of the following additionallimitations: small tissue treatment regions, repositioning the ablationapparatus, and multiple procedures. In particular, the surgeon orclinician may need to reposition the electrical ablation apparatuswithin the tissue treatment region and begin the process anew to treatlarge masses of undesirable tissue. Accordingly, more efficientelectrical ablation apparatuses, systems, and methods for the treatmentof undesirable tissue having reduced or no detrimental thermal effectsto surrounding healthy tissue are desirable.

FIGURES

The various embodiments of electrical ablation devices and methodsthereof described herein may be better understood by considering thefollowing description in conjunction with the accompanying drawings.

FIG. 1 illustrates an electrical ablation system according to certainembodiments described herein.

FIG. 2 illustrates a bipolar electrical ablation system according tocertain embodiments described herein.

FIG. 3 illustrates an electrical ablation system including sensorsaccording to certain embodiments described herein.

FIG. 4 illustrates an electrical ablation system including a temperaturesensor according to certain embodiments described herein.

FIG. 5A is a graphical representation of a series of monophasicelectrical pulses that may be applied to undesirable tissue.

FIG. 5B is a graphical representation of a series of biphasic electricalpulses that may be applied to undesirable tissue.

FIG. 6A illustrates two electrodes in a monophasic electrical ablationsystem according to certain embodiments described herein.

FIG. 6B illustrates two electrodes in a biphasic electrical ablationsystem according to certain embodiments described herein.

FIG. 7 is a graphical representation of a series of electrical pulsesthat may be applied to undesirable tissue to induce irreversibleelectroporation according to certain embodiments described herein.

FIGS. 8A-B are graphical representations of a series of electricalpulses that may be applied to undesirable tissue.

FIG. 9 is a graphical representation of a series of biphasic electricalpulses that may be applied to undesirable tissue to induce irreversibleelectroporation according to certain embodiments described herein.

FIGS. 10A-B are graphical representations of a series of biphasicelectrical pulses that may be applied to undesirable tissue.

FIG. 11 is a graphical representation of a series of electrical pulsesthat may be applied to undesirable tissue.

FIG. 12 illustrates the use of an electrical ablation system accordingto certain embodiments described herein.

FIG. 13 is a photograph of a porcine liver after receiving a series ofelectrical pulses that may be applied to undesirable tissue to induceirreversible electroporation according to certain embodiments describedherein.

FIG. 14 is a graphical representation of electrode temperature during aseries of electrical pulses that may be applied to undesirable tissue toinduce irreversible electroporation according to certain embodimentsdescribed herein.

FIGS. 15A-D include photographs of porcine liver after receiving aseries of electrical pulses that may be applied to undesirable tissue toinduce irreversible electroporation according to certain embodimentsdescribed herein.

FIG. 16 is a graphical representation of a series of electrical pulsesthat may be applied to undesirable tissue.

FIG. 17 is a graph illustrating the area of the necrotic zone of aporcine liver after receiving a series of electrical pulses that may beapplied to undesirable tissue to induce irreversible electroporationaccording to certain embodiments described herein.

FIG. 18A is a graph illustrating the average area of the necrotic zoneof a porcine liver after receiving a series of electrical pulses thatmay be applied to undesirable tissue to induce irreversibleelectroporation according to certain embodiments described herein.

FIG. 18B includes photographs of porcine livers after receiving a seriesof electrical pulses that may be applied to undesirable tissue to induceirreversible electroporation according to certain embodiments describedherein.

FIG. 19 is a graphical representation of a series of electrical pulsesthat may be applied to undesirable tissue.

FIGS. 20A-C include photographs of porcine livers after receiving aseries of electrical pulses that may be applied to undesirable tissue toinduce irreversible electroporation according to certain embodimentsdescribed herein.

FIGS. 21-24 are graphs illustrating the electrode temperature in porcineliver after receiving a series of electrical pulses that may be appliedto undesirable tissue to induce irreversible electroporation accordingto certain embodiments described herein.

FIGS. 25A-C include photographs of porcine livers after receiving aseries of electrical pulses that may be applied to undesirable tissue toinduce irreversible electroporation according to certain embodimentsdescribed herein.

FIGS. 26A-F are graphical representations of simulated necrotic zonesand thermal zones of porcine livers after receiving a series ofelectrical pulses that may be applied to undesirable tissue to induceirreversible electroporation according to certain embodiments describedherein.

FIG. 27 illustrates an electrical ablation system, in a deployed state,according to certain embodiments described herein.

FIGS. 28A-C illustrates electrical ablation systems comprising acontroller according to certain embodiments described herein.

FIGS. 29A-B illustrate an electrical ablation system showing temperaturezones according to certain embodiments described herein.

FIG. 30 is a finite element model of an electrical field in tissue of anelectrical ablation system according to certain embodiments describedherein.

FIG. 31 is a graphical representation of an electric field strengthsufficient to induce irreversible electroporation at body temperature(about 37° C.) according to certain embodiments described herein.

FIG. 32 is a graphical representation of an electric field strengthsufficient to induce irreversible electroporation at an elevatedtemperature (about 55° C.) according to certain embodiments describedherein.

FIG. 33 is a flowchart illustrating an operation of an electricalablation system according to certain embodiments described herein.

DESCRIPTION

Various embodiments are directed to electrical ablation apparatuses,systems, and methods for the treatment of undesirable tissue havingreduced or no detrimental thermal effects to surrounding healthy tissue.

This disclosure describes various elements, features, aspects, andadvantages of various embodiments of electrical ablation devices andmethods thereof. It is to be understood that certain descriptions of thevarious embodiments have been simplified to illustrate only thoseelements, features and aspects that are relevant to a more clearunderstanding of the disclosed embodiments, while eliminating, forpurposes of brevity or clarity, other elements, features and aspects.Any references to “various embodiments,” “some embodiments,” “oneembodiment,” or “an embodiment” generally means that a particularelement, feature and/or aspect described in the embodiment is includedin at least one embodiment. The phrases “in various embodiments,” “insome embodiments,” “in one embodiment,” or “in an embodiment” may notrefer to the same embodiment. Persons having ordinary skill in the art,upon considering the description herein, will recognize that variouscombinations or sub-combinations of the various embodiments and otherelements, features, and aspects may be desirable in particularimplementations or applications. However, because such other elements,features, and aspects may be readily ascertained by persons havingordinary skill in the art upon considering the description herein, andare not necessary for a complete understanding of the disclosedembodiments, a description of such elements, features, and aspects maynot be provided. As such, it is to be understood that the descriptionset forth herein is merely exemplary and illustrative of the disclosedembodiments and is not intended to limit the scope of the invention asdefined solely by the claims.

All numerical quantities stated herein are approximate unless statedotherwise, meaning that the term “about” may be inferred when notexpressly stated. The numerical quantities disclosed herein are to beunderstood as not being strictly limited to the exact numerical valuesrecited. Instead, unless stated otherwise, each numerical value isintended to mean both the recited value and a functionally equivalentrange surrounding that value. At the very least, and not as an attemptto limit the application of the doctrine of equivalents to the scope ofthe claims, each numerical parameter should at least be construed inlight of the number of reported significant digits and by applyingordinary rounding techniques. Notwithstanding the approximations ofnumerical quantities stated herein, the numerical quantities describedin specific examples of actual measured values are reported as preciselyas possible.

All numerical ranges stated herein include all sub-ranges subsumedtherein. For example, a range of “1 to 10” is intended to include allsub-ranges between and including the recited minimum value of 1 and therecited maximum value of 10. Any maximum numerical limitation recitedherein is intended to include all lower numerical limitations. Anyminimum numerical limitation recited herein is intended to include allhigher numerical limitations.

As generally used herein, the terms “proximal” and “distal” generallyrefer to a clinician manipulating one end of an instrument used to treata patient. The term “proximal” generally refers to the portion of theinstrument closest to the clinician. The term “distal” generally refersto the portion located furthest from the clinician. It will be furtherappreciated that for conciseness and clarity, spatial terms such as“vertical,” “horizontal,” “up,” and “down” may be used herein withrespect to the illustrated embodiments. However, surgical instrumentsmay be used in many orientations and positions, and these terms are notintended to be limiting and absolute.

According to certain embodiments, an ablation apparatus may generallycomprise first and second electrodes coupled to an energy sourceoperative to generate and deliver a first sequence of electrical pulsesand a second sequence of electrical pulses to tissue having a necroticthreshold, wherein the first sequence of electrical pulses delivers afirst energy dose that is less than the necrotic threshold to inducethermal heating in the tissue and the second sequence of electricalpulses delivers a second energy dose equal to or greater than thenecrotic threshold to induce cell necrosis in the tissue by irreversibleelectroporation. The necrotic threshold generally refers the electricfield strength that induces cell necrosis by irreversibleelectroporation. The necrotic threshold may relate to at least thefollowing parameters: cell type, temperature, electrical conductivity,pH and tissue perfusion. Table 1 illustrates the necrotic threshold forseveral cell types.

TABLE 1 Cell Type Necrotic Threshold Hepatocyte (healthy porcine)  800V/cm Renal cell (healthy porcine) 1000 V/cm

In certain embodiments, electrical ablation devices may generallycomprise one or more electrodes configured to be positioned into orproximal to undesirable tissue in a tissue treatment region (e.g., atarget site or a worksite). The tissue treatment region may haveevidence of abnormal tissue growth. In general, the electrodes maycomprise an electrically conductive portion (e.g., medical gradestainless steel, gold plated, etc.) and may be configured toelectrically couple to an energy source. Once the electrodes arepositioned into or proximal to the undesirable tissue, an energizingpotential may be applied to the electrodes to create an electric fieldto which the undesirable tissue is exposed. The energizing potential(and the resulting electric field) may be characterized by variousparameters, such as, for example, frequency, amplitude, pulse width(duration of a pulse or pulse length), and/or polarity. Depending on thediagnostic or therapeutic treatment to be rendered, a particularelectrode may be configured either as an anode or a cathode, or aplurality of electrodes may be configured with at least one electrodeconfigured as an anode and at least one other electrode configured as acathode. Regardless of the initial polarity configuration, the polarityof the electrodes may be reversed by reversing the polarity of theoutput of the energy source.

In certain embodiments, a suitable energy source may comprise anelectrical waveform generator. The electrical waveform generator may beconfigured to create an electric field that is suitable to inducethermal heating in the tissue without inducing cell necrosis in thetissue by irreversible electroporation at various electric fieldamplitudes and durations. The electrical waveform generator may beconfigured to create an electric field that is suitable to createirreversible electroporation in undesirable tissue at various electricfield amplitudes and durations. The energy source may be configured todeliver electrical pulses in the form of direct-current (DC) and/oralternating-current (AC) voltage potentials (e.g., time-varying voltagepotentials) to the electrodes. The energy source may also be configuredto reverse the potential between the electrodes. The electrical pulsesmay be characterized by various parameters, such as, for example,frequency, amplitude, pulse width, polarity, total number of pulses,delay between pulses bursts, total number of pulses at a lower voltage,and total number of pulses at high voltage. The undesirable tissue maybe heated by exposure to the electric potential difference across theelectrodes. The undesirable tissue may be ablated by exposure to theelectric potential difference across the electrodes.

In certain embodiments, the apparatuses, systems, and methods may beconfigured for minimally invasive ablation treatment of undesirabletissue through the use of irreversible electroporation. Minimallyinvasive ablation treatment of undesirable tissue may be characterizedby the ability to ablate undesirable tissue in a controlled and focusedmanner having reduced or no thermally damaging effects to thesurrounding healthy tissue. The apparatuses, systems, and methods may beconfigured to ablate undesirable tissue through the use ofelectroporation or electropermeabilization. Electroporation refers tothe application of electric pulses to a cell membrane to cause anincrease in the permeabilization of the cell membrane. The externalelectric field (i.e., electric potential/per unit length) applied to thecell may significantly increase the electrical conductivity andpermeability of the plasma in the cell membrane.

More specifically, the apparatuses, systems, and methods may beconfigured to ablate undesirable tissue through the use of irreversibleelectroporation. Irreversible electroporation refers to the applicationof an electric field of a specific magnitude and duration to a cellmembrane such that the permeabilization of the cell membrane cannot bereversed. One of the primary parameters affecting the transmembranepotential is the potential difference across the cell membrane. Thedestabilizing potential may form pores in the cell membrane when thepotential across the cell membrane exceeds its dielectric strengthcausing the cell to die under a process known as apoptosis and/ornecrosis. Irreversible electroporation may induce localized heating ofthe tissue surrounding the electrodes. Irreversible electroporation maylead to cell death without inducing a significant amount of heat in thecell membrane.

The application of irreversible electroporation pulses to cells may bean effective way for ablating large volumes of undesirable tissue withno or minimal detrimental thermal effects to the surrounding healthytissue. Without wishing to be bound to any particular theory, it isbelieved that irreversible electroporation destroys cells with no orminimal heat, and thus, may not destroy the cellular support structureor regional vasculature. A destabilizing irreversible electroporationpulse, suitable to cause cell death without inducing a significantamount of thermal damage to the surrounding healthy tissue, may haveamplitude in the range of several hundred to several thousand volts andmay be generally applied across biological membranes over a distance ofseveral millimeters, for example, for a relatively long duration of 1 μsto 100 ms. Thus, the undesirable tissue may be ablated in-vivo throughthe delivery of destabilizing electric fields by quickly causing cellnecrosis.

The apparatuses, systems, and methods for electrical ablation therapymay be adapted for use in minimally invasive surgical procedures toaccess the tissue treatment region in various anatomic locations, suchas, for example, the brain, lungs, breast, liver, gall bladder,pancreas, prostate gland, and various internal body lumen defined by theesophagus, stomach, intestine, colon, arteries, veins, anus, vagina,cervix, fallopian tubes, and the peritoneal cavity. Minimally invasiveelectrical ablation devices may be introduced to the tissue treatmentregion though a small opening formed in the patient's body using atrocar or through a natural body orifice such as the mouth, anus, orvagina using translumenal access techniques known as Natural OrificeTranslumenal Endoscopic Surgery (NOTES)™. Once the electrical ablationdevices (e.g., electrodes) are located into or proximal to theundesirable tissue in the treatment region, electric field potentialsmay be applied by the energy source to the undesirable tissue. Theelectrical ablation devices may comprise portions that may be insertedinto the tissue treatment region percutaneously (e.g., where access toinner organs or other tissue is done via needle-puncture of the skin).Other portions of the electrical ablation devices may be introduced intothe tissue treatment region endoscopically (e.g., laparoscopicallyand/or thoracoscopically) through trocars or channels of the endoscope,through small incisions, or transcutaneously (e.g., where electricpulses are delivered to the tissue treatment region through the skin).An electrical ablation device is described in commonly owned U.S. PatentPublication No. 2010/0179530, entitled, “ELECTRICAL ABLATION DEVICES”filed Jan. 12, 2009.

FIG. 1 illustrates one embodiment of an electrical ablation system 10.The electrical ablation system 10 may be employed to ablate undesirabletissue, such as, for example, diseased tissue, cancer, malignant andbenign tumors, masses, lesions, and other abnormal tissue growths in atissue treatment region using electrical energy. The electrical ablationsystem 10 may be configured to treat a number of lesions andostepathologies comprising metastatic lesions, tumors, fractures,infected sites, and inflamed sites in a tissue treatment region usingelectrical energy. The electrical ablation system 10 may be configuredto be positioned within a patient's natural body orifice, e.g., themouth, anus, and vagina, and/or advanced through internal body lumen orcavities, e.g., the esophagus, stomach, intestines, colon, cervix, andurethra, to reach the tissue treatment region. The electrical ablationsystem 10 may be configured to be positioned and passed through a smallincision or keyhole formed through the patient's skin or abdominal wallusing a trocar to reach the tissue treatment region. The tissuetreatment region may be located in the patient's brain, lung, breast,liver, gall bladder, pancreas, prostate gland, various internal bodylumen defined by the esophagus, stomach, intestine, colon, arteries,veins, anus, vagina, cervix, fallopian tubes, and the peritoneal cavity.The electrical ablation system 10 may be used in conjunction withendoscopic, laparoscopic, thoracoscopic, open surgical procedures viasmall incisions or keyholes, percutaneous techniques, transcutaneoustechniques, and/or external non-invasive techniques, and anycombinations thereof.

Once positioned into or proximate the tissue treatment region, theelectrical ablation system 10 may be actuated (e.g., energized) toablate the undesirable tissue. In one embodiment, the electricalablation system 10 may be configured to treat diseased tissue in thegastrointestinal tract, esophagus, lung, and/or stomach that may beaccessed orally. In another embodiment, the electrical ablation system10 may be adapted to treat undesirable tissue in the liver or otherorgans that may be accessible using translumenal access techniques, suchas, for example, NOTES™ techniques where the electrical ablation devicesmay be initially introduced through a natural body orifice and thenadvanced to the tissue treatment site by puncturing the walls ofinternal body lumen. In various embodiments, the electrical ablationsystem 10 may be adapted to treat undesirable tissue in the brain, lung,breast, liver, gall bladder, pancreas, or prostate gland, using one ormore electrodes positioned percutaneously, transcutaneously,translumenally, minimally invasively, and/or through open surgicaltechniques, or any combination thereof.

In one embodiment, the electrical ablation system 10 may be employed inconjunction with a flexible endoscope 12, as well as a rigid endoscope,laparoscope, or thoracoscope, such as the GIF-100 model available fromOlympus Corporation. In one embodiment, the endoscope 12 may beintroduced to the tissue treatment region trans-anally through thecolon, trans-orally through the esophagus and stomach, trans-vaginallythrough the cervix, transcutaneously, or via an external incision orkeyhole formed in the abdomen in conjunction with a trocar. Theelectrical ablation system 10 may be inserted and guided into orproximate the tissue treatment region using the endoscope 12. In otherembodiments, the endoscope 12 is not utilized, and instead othertechniques, such as, for example, ultrasound or a computerizedtomography (CT) scan, may be used to determine proper instrumentplacement during the procedure.

In the embodiment illustrated in FIG. 1, the endoscope 12 comprises anendoscope handle 34 and an elongate relatively flexible shaft 32. Thedistal end of the flexible shaft 32 may comprise a light source and aviewing port. Optionally, the flexible shaft 32 may define one or morechannels for receiving various instruments therethrough, such as, forexample, electrical ablation devices. Images within the field of view ofthe viewing port may be received by an optical device, such as, forexample, a camera comprising a charge coupled device (CCD) usuallylocated within the endoscope 12, and transmitted to a display monitor(not shown) outside the patient. In one embodiment, the electricalablation system 10 may comprise a plurality of electrical conductors 18,a hand piece 16 comprising an activation switch 62, and an energy source14, such as, for example, an electrical waveform generator, electricallycoupled to the activation switch 62 and the electrical ablation device20. The electrical ablation device 20 may comprise a relatively flexiblemember or shaft 22 that may be introduced to the tissue treatment regionusing any of the techniques discussed above, such as, an open incisionand a trocar, through one of more of the channels of the endoscope 12,percutaneously, or transcutaneously.

In one embodiment, one or more electrodes (e.g., needle electrodes,balloon electrodes), such as first and second electrodes 24 a,b mayextend out from the distal end of the electrical ablation device 20. Inone embodiment, the first electrode 24 a may be configured as thepositive electrode and the second electrode 24 b may be configured asthe negative electrode. The first electrode 24 a may be electricallyconnected to a first electrical conductor 18 a, or similar electricallyconductive lead or wire, which may be coupled to the positive terminalof the energy source 14 through the activation switch 62. The secondelectrode 24 b may be electrically connected to a second electricalconductor 18 b, or similar electrically conductive lead or wire, whichmay be coupled to the negative terminal of the energy source 14 throughthe activation switch 62. The electrical conductors 18 a,b may beelectrically insulated from each other and surrounding structures,except for the electrical connections to the respective electrodes 24a,b.

In certain embodiments, the electrical ablation device 20 may beconfigured to be introduced into or proximate the tissue treatmentregion using the endoscope 12 (laparoscope or thoracoscope), opensurgical procedures, and/or external and non-invasive medicalprocedures. The electrodes 24 a,b may be referred to herein asendoscopic or laparoscopic electrodes, although variations thereof maybe inserted transcutaneously or percutaneously. In various embodiments,one or both electrodes 24 a,b may be adapted and configured to slideablymove in and out of a cannula, lumen, or channel defined within theflexible shaft 22.

When the electrodes 24 a,b are positioned at the desired location intoor proximate the tissue treatment region, the electrodes 24 a,b may beconnected to or disconnected from the energy source 14 by actuating orde-actuating the activation switch 62 on the hand piece 16. Theactivation switch 62 may be operated manually or may be mounted on afoot switch (not shown), for example. The electrodes 24 a,b may deliverelectric field pulses to the undesirable tissue. The electric fieldpulses may be characterized by various parameters, such as, for example,pulse shape, amplitude, frequency, pulse width, polarity, total numberof pulses and duration. The electric field pulses may be sufficient toinduce thermal heating in the undesirable tissue without inducingirreversible electroporation in the undesirable tissue. The electricfield pulses may be sufficient to induce irreversible electroporation inthe undesirable tissue. The induced potential may depend on a variety ofconditions, such as, for example, tissue type, cell size, and electricalfield pulse parameters. The transmembrane potential of a specific tissuetype may primarily depend on the amplitude of the electric field andpulse width.

In certain embodiments, a protective sleeve or sheath 26 may be slidablydisposed over the flexible shaft 22 and within a handle 28. In anotherembodiment, the sheath 26 may be slidably disposed within the flexibleshaft 22 and the handle 28. The sheath 26 may be slideable and may belocated over the electrodes 24 a,b to protect the trocar and preventaccidental piercing when the electrical ablation device 20 is advancedtherethrough. One or both of the electrodes 24 a,b may be adapted andconfigured to slideably move in and out of a cannula, lumen, or channelformed within the flexible shaft 22. One or both of the electrodes 24a,b may be fixed in place. One of the electrodes 24 a,b may provide apivot about which the other electrode may be moved in an arc to otherpoints in the tissue treatment region to treat larger portions of thediseased tissue that cannot be treated by fixing both of the electrodes24 a,b in one location. In one embodiment, one or both of the electrodes24 a,b may be adapted and configured to slideably move in and out of aworking channel formed within a flexible shaft 32 of the endoscope 12 ormay be located independently of the endoscope 12.

In one embodiment, the first and second electrical conductors 18 a,b maybe provided through the handle 28. The first electrode 24 a may beslideably moved in and out of the distal end of the flexible shaft 22using a slide member 30 to retract and/or advance the first electrode 24a. The second electrode 24 b may be slideably moved in and out of thedistal end of the flexible shaft 22 using the slide member 30 or adifferent slide member to retract and/or advance the second electrode 24b. One or both electrodes 24 a,b may be coupled to the slide member 30,or additional slide members, to advance and retract the electrodes 24a,b and position the electrodes 24 a,b. In this manner, the first andsecond electrodes 24 a,b, which may be slidably movable within thecannula, lumen, or channel defined within the flexible shaft 22, may beadvanced and retracted with the slide member 30. As shown in FIG. 1, thefirst electrical conductor 18 a coupled to the first electrode 24 a maybe coupled to the slide member 30. In this manner, the first electrode24 a, which is slidably movable within the cannula, lumen, or channelwithin the flexible shaft 22, may be advanced and retracted with theslide member 30. In one embodiment, various slide members, such as theslide member 30, may be rotatable. Thus rotation of the slide member 30may rotate the corresponding electrode(s) at the distal end of theelectrical ablation device 20.

In various other embodiments, transducers or sensors 29 may be locatedin the handle 28 (or other suitable location) of the electrical ablationdevice 20 to sense the force with which the electrodes 24 a,b penetratethe tissue in the tissue treatment region. This feedback information maybe useful to determine whether one or both of the electrodes 24 a,b havebeen properly inserted in the tissue treatment region. As isparticularly well known, cancerous tumor tissue tends to be denser thanhealthy tissue, and thus greater force may be typically required toinsert the electrodes 24 a,b therein. The transducers or sensors 29 mayprovide feedback to the operator, surgeon, or clinician to physicallysense when the electrodes 24 a,b are placed within the cancerous tumor.The feedback information provided by the transducers or sensors 29 maybe processed and displayed by circuits located either internally orexternally to the energy source 14. The sensor 29 readings may beemployed to determine whether the electrodes 24 a,b have been properlylocated within the cancerous tumor thereby assuring that a suitablemargin of error has been achieved in locating the electrodes 24 a,b. Thesensor 29 readings may also be employed to determine whether the pulseparameters need to be adjusted to achieve a desired result, such as, forexample, reducing the intensity of muscular contractions in the patient.

Referring to FIG. 2, in one embodiment, the electrical ablation device20 may comprise a first flexible shaft 22 a housing the first electrode24 a and a second flexible shaft 22 b housing the second electrode 24 b.The electrical ablation device 20 may comprise a first protective sleeveor sheath (not shown) disposed over at least one of the first flexibleshaft 22 a and second flexible shaft 22 b. The electrical ablationdevice 20 may comprise a first protective sleeve or sheath (not shown)disposed over the first flexible shaft 22 a and a second protectivesleeve or sheath (not shown) disposed over the second flexible shaft 22b. The length of the first flexible shaft 22 a may be different than thelength of the second flexible shaft 22 b. The length of the firstflexible shaft 22 a may be greater than or equal to the length of thesecond flexible shaft 22 b. The length of the first protective sleeve orsheath may be different than the length of the second protective sleeveor sheath. The length of the first protective sleeve or sheath may begreater than or equal to the length of the second protective sleeve orsheath. In one embodiment, an electrical ablation device for biphasicpulses may have the first flexible shaft 22 a disposed over the firstelectrode 24 a having a positive polarity and the second flexible shaft22 b disposed over the second electrode 24 b having a negative polarity,and wherein the length of the first flexible shaft 22 a is greater thanthe length of the second flexible shaft 22 b.

Referring to FIGS. 1 and 3, the electrical ablation device 20 may beconfigured to measure at least one of the temperature and pressure. Thetransducers or sensors 29 may comprise at least one of a temperaturesensor and a pressure sensor. In certain embodiments, at least one of atemperature sensor and pressure sensor may be located in or proximatethe electrical ablation system 10. The temperature sensor and/orpressure sensor may be located within the handle 28. The temperaturesensor and/or pressure sensor may be located within the protectivesleeve or sheath 26. The temperature sensor 25 and/or pressure sensor 27may be located within the flexible shaft 22. The temperature sensor 25and/or pressure sensor 27 may be located at the distal end of theflexible shaft 22. The protective sleeve or sheath 26 and/or theflexible shaft 22 may comprise one or more vents 31 configured formeasuring at least one of the temperature and pressure of the tissuetreatment region. The temperature sensor and/or pressure sensor may belocated within the electrodes 24 a,b. The pressure sensor 27 may beadjacent to at least one of the vents 31. In one embodiment, thepressure sensor 27 may be adjacent at least one of the vents 31 and thetemperature sensor 25 may be located at the distal end of the flexibleshaft 22. FIG. 4 is a photograph of an electrical ablation devicecomprising an optical temperature sensor 29 located in the electrode 24a at the distal end of the flexible shaft 22.

In certain embodiments, the temperature sensor and/or pressure sensormay be separate from the electrical ablation system 10. The electricalablation device 20 may include the temperature sensor 25 and thepressure sensor may be separate from the electrical ablation system 10.The electrical ablation device 20 may include the pressure sensor 27 andthe temperature sensor may be separate from the electrical ablationsystem 10.

According to certain embodiments, the temperature sensor may measure thetemperature of the tissue treatment region. The temperature sensor maymeasure the temperature of the undesirable tissue. The temperaturesensor may measure the temperature of the tissue surrounding theelectrodes. The temperature sensor may measure the temperature before,during, and/or after treatment. The temperature sensor may measure thetemperature before the first sequence of electrical pulses is deliveredto the tissue. The temperature sensor may measure the temperature afterthe first sequence of electrical pulses is delivered to the tissue. Thetemperature sensor may measure the temperature before the secondsequence of electrical pulses is delivered to the tissue. Thetemperature sensor may measure the temperature after the second sequenceof electrical pulses is delivered to the tissue.

According to certain embodiments, the pressure sensor may measure thepressure of the tissue treatment region. The pressure sensor may measurethe pressure of the space between the electrodes. The pressure sensormay measure the pressure surrounding the electrodes. The pressure sensormay measure the pressure before, during, and/or after treatment. Thepressure sensor may measure the pressure before the first sequence ofelectrical pulses is delivered to the tissue. The pressure sensor maymeasure the pressure after the first sequence of electrical pulses isdelivered to the tissue. The pressure sensor may measure the pressurebefore the second sequence of electrical pulses is delivered to thetissue. The pressure sensor may measure the pressure after the secondsequence of electrical pulses is delivered to the tissue.

The temperature sensor and pressure sensor may provide feedback to theoperator, surgeon, or clinician to apply an electric field pulse to theundesirable tissue. The pressure and/or temperature information may beuseful to determine whether the undesirable tissue may be treated havingreduced or no detrimental thermal effects to surrounding healthy tissue.The feedback information provided by the transducers or sensors 29 maybe processed and displayed by circuits located either internally orexternally to the energy source 14.

In one embodiment, the input to the energy source 14 may be connected toa commercial power supply by way of a plug (not shown). The output ofthe energy source 14 is coupled to the electrodes 24 a,b, which may beenergized using the activation switch 62 on the hand piece 16, or anactivation switch mounted on a foot activated pedal (not shown). Theenergy source 14 may be configured to produce electrical energy suitablefor thermal heating and/or electrical ablation.

In one embodiment, the electrodes 24 a,b may be adapted and configuredto electrically couple to the energy source 14 (e.g., generator,waveform generator). Once electrical energy is coupled to the electrodes24 a,b, an electric field may be formed at a distal end of theelectrodes 24 a,b. The energy source 14 may be configured to generateelectric pulses at a predetermined frequency, amplitude, pulse width,and/or polarity that are suitable to induce thermal heating in theundesirable tissue in the treatment region. The energy source 14 may beconfigured to generate electric pulses at a predetermined frequency,amplitude, pulse width, and/or polarity that are suitable to induceirreversible electroporation to ablate substantial volumes ofundesirable tissue in the treatment region. For example, the energysource 14 may be configured to deliver DC electric pulses having apredetermined frequency, amplitude, pulse width, and/or polaritysuitable to induce thermal heating in the undesirable tissue in thetreatment region. For example, the energy source 14 may be configured todeliver DC electric pulses having a predetermined frequency, amplitude,pulse width, and/or polarity suitable to induce irreversibleelectroporation to ablate substantial volumes of undesirable tissue inthe treatment region. The DC pulses may be positive or negative relativeto a particular reference polarity. The polarity of the DC pulses may bereversed or inverted from positive-to-negative or negative-to-positive apredetermined number of times to induce irreversible electroporation toablate substantial volumes of undesirable tissue in the treatmentregion.

In one embodiment, a timing circuit may be coupled to the output of theenergy source 14 to generate electric pulses. The timing circuit maycomprise one or more suitable switching elements to produce the electricpulses. For example, the energy source 14 may produce a series of melectric pulses (where m is any positive integer) of sufficientamplitude and duration less than the necrotic threshold to inducethermal heating in the undesirable tissue when the m electric pulses areapplied to the electrodes 24 a,b and a series of n electric pulses(where n is any positive integer) of sufficient amplitude and durationto induce irreversible electroporation suitable for tissue ablation whenthe n electric pulses are applied to the electrodes 24 a,b. In oneembodiment, the electric pulses may have a fixed or variable pulsewidth, amplitude, and/or frequency.

The electrical ablation device 20 may be operated either in bipolarmode, i.e., monophasic, or monopolar mode, i.e., biphasic. In monopolarmode, the surface area of the electrodes may be different, and adispersive pad (i.e., a ground pad) may be positioned relatively farfrom the “active” electrode. In bipolar mode, the surface area of theelectrodes may be similar, and electrodes may be positioned relativelyclose together. FIG. 5A is a graphical representation of a series ofmonophasic electrical pulses having the same polarity in which eachpulse has an amplitude of +3,000 VDC. In other words, the polarity maynot change between the electrodes for monophasic electrical pulses. FIG.6A illustrates two electrodes 24 a,b in a monophasic electrical ablationsystem in which the first electrode 24 a has a positive polarityrelative to the other electrode 24 b. A ground pad may be substitutedfor one of the electrodes.

FIG. 5B is a graphical representation of a series of biphasic electricalpulses having opposite polarity in which the first electrical pulse hasan amplitude of +3,000 VDC and the second electrical pulse has anamplitude of −3,000 VDC. FIG. 6B illustrates two electrodes 24 a,b in abipolar electrical ablation system in which the polarity of eachelectrodes 24 a,b alternates. In bipolar mode, the first electrode 24 amay be electrically connected to a first polarity and the secondelectrode 24 b may be electrically connected to the opposite polarity.In monophasic mode, the first electrode 24 a may be coupled to aprescribed voltage and the second electrode 24 b may be set to ground.The energy source 14 may be configured to operate in either the biphasicor monophasic modes with the electrical ablation system 10. In biphasicmode, the first electrode 24 a may be electrically connected to aprescribed voltage of one polarity and the second electrode 24 b may beelectrically connected to a prescribed voltage of the opposite polarity.The polarity may alternate between the electrodes for biphasicelectrical pulses. When more than two electrodes are used, the polarityof the electrodes may be alternated so that any two adjacent electrodesmay have either the same or opposite polarities. In bipolar mode, thenegative electrode of the energy source 14 may be coupled to animpedance simulation circuit. According to certain embodiments, amonophasic output or a biphasic output may be applied to a monopolarelectrode orientation or a bipolar electrode orientation.

In one embodiment, the energy source 14 may be configured to produce RFwaveforms at predetermined frequencies, amplitudes, pulse widths, and/orpolarities suitable for thermal heating and/or electrical ablation ofcells in the tissue treatment region. One example of a suitable RFenergy source may be a commercially available conventional,bipolar/monopolar electrosurgical RF generator, such as Model Number ICC350, available from Erbe, GmbH. In one embodiment, the energy source maycomprise a microwave energy source configured to produce microwavewaveforms at predetermined frequencies, amplitudes, pulse widths, and/orpolarities suitable for thermal heating and/or electrical ablation ofcells in the tissue treatment region. The microwave power source, suchas MicroThermx, available from Boston Scientific Corp., may be coupledto a microwave antenna providing microwave energy in the frequency rangefrom 915 MHz to 2.45 GHz.

In one embodiment, the energy source 14 may be configured to producedestabilizing electrical potentials (e.g., fields) suitable to inducethermal heating and/or irreversible electroporation. The destabilizingelectrical potentials may be in the form of biphasic/monophasic DCelectric pulses suitable for inducing thermal heating and/orirreversible electroporation to ablate tissue undesirable tissue withthe electrical ablation device 20. A commercially available energysource suitable for generating thermal heating and/or irreversibleelectroporation electric field pulses in bipolar or monopolar mode is apulsed DC generator such as Model Number ECM 830, available from BTXMolecular Delivery Systems Boston, Mass. In bipolar mode, the firstelectrode 24 a may be electrically coupled to a first polarity and thesecond electrode 25 may be electrically coupled to a second (e.g.,opposite) polarity of the energy source 14. Biphasic/monophasic electricpulses may be generated at a variety of frequencies, amplitudes, pulsewidths, and/or polarities. Unlike RF ablation systems, which may requirehigh power and energy levels delivered into the tissue to heat andthermally destroy the tissue, irreversible electroporation may requirevery little energy applied to the tissue to heat and kill the cells ofthe undesirable tissue using electric field potentials rather than heat.Accordingly, irreversible electroporation systems may avoid thedetrimental thermal effects caused by RF ablation systems.

In certain embodiments, the energy source may comprise a wirelesstransmitter to deliver energy to the electrodes using wireless energytransfer techniques via one or more remotely positioned antennas. Thoseskilled in the art will appreciate that wireless energy transfer orwireless power transmission refers to the process of transmittingelectrical energy from an energy source to an electrical load withoutinterconnecting wires. In one embodiment, the energy source 14 may becoupled to the first and second electrodes 24 a,b by a wired or awireless connection. In a wired connection, the energy source 14 may becoupled to the electrodes 24 a,b by way of the electrical conductors 18a,b, as shown. In a wireless connection, the electrical conductors 18a,b may be replaced with a first antenna (not shown) coupled the energysource 14 and a second antenna (not shown) coupled to the electrodes 24a,b, wherein the second antenna may be remotely located from the firstantenna. In one embodiment, the energy source may comprise a wirelesstransmitter to deliver energy to the electrodes using wireless energytransfer techniques via one or more remotely positioned antennas. Aspreviously discussed, wireless energy transfer or wireless powertransmission is the process of transmitting electrical energy from theenergy source 14 to an electrical load, e.g., the abnormal cells in thetissue treatment region, without using the interconnecting electricalconductors 18 a,b. An electrical transformer is the simplest example ofwireless energy transfer. The primary and secondary circuits of atransformer may not be directly connected and the transfer of energy maytake place by electromagnetic coupling through a process known as mutualinduction. Power also may be transferred wirelessly using RF energy.

In one embodiment, the energy source 14 may be configured to generate DCelectric pulses at frequencies in the range of about 1 Hz to about10,000 Hz, amplitudes in the range of about ±100 VDC to about ±6,000VDC, and pulse width in the range of about 1 μs to about 100 ms. Thepolarity of the electric potentials coupled to the electrodes 24 a,b maybe reversed during thermal heating and/or electrical ablation therapy.For example, initially, the electric pulses may have a positive polarityand an amplitude in the range of about +100 VDC to about +6,000 VDC.Subsequently, the polarity of the DC electric pulses may be reversedsuch that the amplitude is in the range of about −100 VDC to about−6,000 VDC. In one embodiment, the undesirable cells in the tissuetreatment region may be electrically ablated with DC pulses suitable toinduce irreversible electroporation at frequencies of about 10 Hz toabout 100 Hz, amplitudes in the range of about +700 VDC to about +3,000VDC, and pulse widths of about 10 μs to about 50 μs. In anotherembodiment, the abnormal cells in the tissue treatment region may beelectrically ablated with an electrical waveform having an amplitude ofabout +500 VDC and pulse duration of about 20 μs delivered at a pulseperiod T or repetition rate, frequency f=1/T, of about 10 Hz. Withoutwishing to be bound to any particular theory, it is believed that anelectric field strength of about 800 V/cm to 1,000 V/cm is suitable fordestroying living tissue by inducing irreversible electroporation.

The electrodes 24 a,b may have a diameter or radius from 0.5 mm to 1.5mm, such as, for example, 0.5 mm, 0.75 mm, 1 mm, and 1.5 mm. In variousembodiments, the diameter of the first electrode 24 a may by differentfrom the diameter of the second electrode 24 b. The electrode spacingmay be from 0.5 cm to 3 cm. In various embodiments, the distance fromthe first electrode 24 a to the second electrode 24 b may be from 0.5 cmto 3 cm, such as, for example, 1 cm, 1.5 cm, 2.0 cm, and 3 cm. In oneembodiment, the electrical ablation device 20 may comprise multipleneedle electrodes.

According to certain embodiments, the electrical ablation device 20 maybe introduced into the tissue treatment region through a trocar, forexample, or inserted to a tissue treatment region transcutaneously,percutaneously, or other suitable techniques. In one embodiment, thecannula, lumen, or channel defined within the flexible shaft 22 maycomprise a cutting edge, such as a bevel or other sharp edge, to aid inthe puncturing/piercing of tissue.

According to certain embodiments, a method of treating tissue maygenerally comprise obtaining an ablation apparatus comprising first andsecond electrodes coupled to an energy source operative to generate anddeliver a first sequence of electrical pulses and a second sequence ofelectrical pulses to tissue having a necrotic threshold, wherein thefirst sequence of electrical pulses deliver a first energy dose that isless than the necrotic threshold to induce thermal heating in the tissueand the second sequence of electrical pulses deliver a second energydose equal to or greater than the necrotic threshold to induce cellnecrosis in the tissue by irreversible electroporation, inserting thefirst electrode into a mass of tissue having a necrotic threshold,applying a first sequence of electrical pulses to the first electrodeless than the necrotic threshold to induce thermal heating, applying asecond sequence of electrical pulses to the first electrode to inducecell necrosis by irreversible electroporation, and applying a groundpotential to the second electrode, wherein the ablation apparatus isoperative to reduce the necrotic threshold of the tissue relative to acorresponding ablation apparatus having an energy source configured todeliver a first sequence of electrical pulses to induce cell necrosis byirreversible electroporation.

In certain embodiments, the ablation apparatus may reduce the necroticthreshold of the cell membrane by 0-500 mV, such as, for example, 50-400mV, 100-300 mV, and 150-250 mV relative to a corresponding ablationapparatus having an energy source configured to deliver a first sequenceof electrical pulses to induce cell necrosis by irreversibleelectroporation. The ablation apparatus may reduce the necroticthreshold by 0-50%, such as, for example, 10%, 20%, 30%, and 40%,relative to a corresponding ablation apparatus having an energy sourceconfigured to deliver a first sequence of electrical pulses to inducecell necrosis by irreversible electroporation.

According to certain embodiments, a method of treating tissue maygenerally comprise applying a first sequence of electrical pulses toundesirable tissue to induce thermal heating and applying a secondsequence of electrical pulses to undesirable tissue to induce cellnecrosis by irreversible electroporation. The first energy dose may beless than the necrotic threshold, less than the critical membranevoltage, less than the threshold for muscle contraction, and/or lessthan the threshold for ventricular arrhythmia. The first energy dose mayreduce the necrotic threshold of the tissue. The first energy dose mayreduce the necrotic threshold of the cell membrane by 0-500 mV, such as,for example, 50-400 mV, 100-300 mV, and 150-250 mV. The first energydose may reduce the necrotic threshold by 0-50%, such as, for example,10%, 20%, 30%, and 40%. The first energy dose and/or second energy dosemay be synchronized with the patient's cardiac cycle to preventventricular arrhythmia. According to certain embodiments, the ablationapparatus may reduce the risk of ventricular arrhythmia relative to asimilar ablation apparatus comprising a first sequence of electricalpulses to induce cell necrosis in the tissue by irreversibleelectroporation.

In certain embodiments, a method of treating tissue may generallycomprise inserting the first electrode into a mass of tissue having amembrane potential and a necrotic threshold, applying a first sequenceof electrical pulses to the first electrode less than the necroticthreshold to induce thermal heating, applying a second sequence ofelectrical pulses to the first electrode to induce cell necrosis byirreversible electroporation, and applying a ground potential to thesecond electrode. In one embodiment, the method may comprise re-applyingthe sequence of electrical pulses to the first electrode. In oneembodiment, the energy source may be operative to generate and deliver asequence interval between the first sequence and second sequence. Thefirst sequence of electrical pulses may comprise a series of first pulsetrains each having a first pulse train amplitude, a first pulse trainpulse width, and a first pulse train frequency, and the second sequenceof electrical pulses may comprise a series of second pulse trains eachcomprising a second pulse train amplitude, a second pulse train pulsewidth, and a second pulse train frequency. The first pulse trains maycomprise a plurality of first pulses each having a first amplitude, afirst pulse width, and a first frequency, and each of the second pulsetrains may comprise a plurality of second pulses each having a secondamplitude, a second pulse width, and a second frequency. Each of thefirst pulses and the second pulses may independently have amplitudes inthe range of about ±100 VDC to about ±10,000 VDC, pulse widths in therange of about 1 μs to about 100 ms, and frequencies in the range ofabout 1 Hz to about 10,000 Hz.

FIG. 7 is a graphical representation of a first sequence of electricalpulses that deliver a first energy dose less than the necrotic thresholdto induce thermal heating and a second sequence of electrical pulsesthat deliver a second energy dose to induce cell necrosis byirreversible electroporation. Time (t) is shown along the horizontalaxis and voltage (VDC) is shown along the vertical axis. Initially, theundesirable tissue may be exposed to a series of first pulse trains 70each having a first pulse train amplitude V₁, a first pulse train pulsewidth T_(w1), and a first pulse train frequency F₁ sufficient to inducethermal heating in the tissue. When the tissue achieves a predeterminedtemperature and/or pressure, the undesirable tissue 48 may be exposed toa series of second pulse trains 72. The undesirable tissue may beexposed to a series of second pulse trains 72 each having a second pulsetrain amplitude V₂, a second pulse train pulse width T_(w2), and asecond pulse train frequency F₂ sufficient to induce thermal necrosisand/or irreversible electroporation in the tissue. The series of firstpulse trains 70 may comprise at least one first pulse train and theseries of second pulse trains 72 may comprise at least one second pulsetrain.

In certain embodiments, at least one of the first pulse train amplitudeV₁, the first pulse train pulse width T_(w1), and the first pulse trainfrequency F₁ may be greater than or equal to the second pulse trainamplitude V₂, the second pulse train pulse width T_(w2), and the secondpulse train frequency F₂. The first pulse train amplitude V₁ may be lessthan or equal to the second pulse train amplitude V₂. The first pulsetrain pulse width T_(w1) may be less than, greater than, or equal to thesecond pulse train pulse width T_(w2). The first pulse train frequencyF₁ may be greater than or equal to the second pulse train frequency F₂.The first sequence duration D₁ may be greater than or equal to thesecond sequence duration D₂. The total number of first pulse trains maybe 70 may be greater than or equal to the total number of second pulsetrains 72. In one embodiment, the first pulse train amplitude may beless than the second pulse train amplitude, the first pulse train pulsewidth may be equal to the second pulse train pulse width, and the firstpulse train frequency may be greater than the second pulse trainfrequency. The energy source may operative to generate and deliver asequence interval S_(I) between the first sequence and second sequence.The sequence interval may be from 0 to 10 seconds, 1 second to 10seconds, such as, for example, 0.5 seconds, 1 second, and 2 seconds.

FIGS. 8A-B are graphical representations of a first pulse train 70 and asecond pulse train 72, respectively. Time (t) is shown along thehorizontal axis and voltage (VDC) is shown along the vertical axis. Eachof the first pulse trains 70 may comprise a plurality of first pulses 70a each having a first amplitude v₁, a first pulse width t_(w1), and afirst frequency f₁, and each of the second pulse trains 72 may comprisea plurality of second pulses 72 a each having a second amplitude v₂, asecond pulse width t_(w2), and a second frequency f₂. The first pulsesand the second pulses may be each independently characterized by firstand second amplitudes in the range of about ±100 VDC to about ±10,000VDC, first and second pulse widths in the range of about 1 μs to about100 ms, and first and second frequencies in the range of about 1 Hz toabout 10,000 Hz. In one embodiment, the energy source 14 may beconfigured to generate and deliver DC first pulses and the second pulsesat frequencies in the range of 1 Hz to 10,000 Hz, amplitudes in therange of ±100 VDC to ±3000 VDC, and pulse width in the range of about 1μs to about 100 ms. The first amplitude v₁ may be less than or equal tothe second amplitude v₂. The first pulse width t_(w1) may be less than,greater than, or equal to the second pulse width t_(w2). The firstfrequency f₁ may be greater than or equal to the second frequency f₂.The total number of first pulses may be greater than or equal to thetotal number of second pulses. In one embodiment, the first amplitudemay be less than the second amplitude, the first pulse width may beequal to the second pulse width, and the first frequency may be equal tothe second frequency.

In one embodiment, a first pulse train 70 comprising high-voltage DCelectrical pulses having a first pulse train amplitude V₁ of 500 VDC anda first pulse train pulse width T_(w1) of 50 μs may be applied to thefirst and second electrodes 24 a,b by the energy source 14 to inducethermal heating in the tissue. A second pulse train 72 comprising higherhigh-voltage DC electrical pulses having a second pulse train amplitudeV₂ of 1000 V and a second pulse train pulse width T_(w2) of 50 μs may beapplied to the first and second electrodes 24 a,b by the energy source14 to induce cell necrosis in the tissue by irreversibleelectroporation. In one embodiment, the polarity of at least one of thefirst pulse train 70 and the second pulse train 72 may be inverted orreversed by the energy source 14 during the thermal heating and/orablation processes.

In one embodiment, the series of first pulses 70 may comprises a singlepulse 70 a or multiple pulses having a first amplitude v₁ of 500 VDC, afirst pulse width t_(w1) of 10 μs to 15 μs, and a period t₁ of about 100ms (f₁=10 Hz) sufficient to induce thermal heating in the tissueproximate the electrode-tissue-interface immediately surrounding therespective electrodes 24 a,b. In one embodiment, the series of secondpulses 72 may comprise 20 to 40 electric pulses 72 a having a secondamplitude v₂ of 1000 VDC, a second pulse width t_(w2) of 10 μs to 15 μs,and a period t₂ of 100 μs (f₂=10,000 Hz) sufficient to induceirreversible electroporation. In one embodiment, the series of secondpulses 72 may comprise multiple electrical pulses, for example, 20 to 40electric pulses, having a second amplitude v₂ of 1500 to 3000 VDC, asecond pulse width t_(w2) of 10 μs to 50 μs, and a period t₂ of 10 μs.In one embodiment, the undesirable cells in the tissue treatment regionmay be electrically ablated with DC pulses suitable to induceirreversible electroporation at frequencies of about 10 Hz to about 100Hz, amplitudes in the range of about +700 VDC to about +1500 VDC, andpulse widths of about 10 μs to about 50 μs. In another embodiment, theabnormal cells in the tissue treatment region may be heated with anelectrical waveform having an amplitude of about +500 VDC and pulseduration of about 20 ms delivered at a pulse period or repetition rate,frequency f=1/T, of about 10 Hz.

In certain embodiments, a total dose average power may comprise theaverage power of the first sequence of electrical pulses, the averagepower of the second sequence of electrical pulses, and the sequenceinterval. The first energy dose may have an average power from 5 Wattsto 10 Watts. The second first energy dose may have an average power from10 Watts to 15 Watts. The total dose average power may be 1 Watt to 5Watts. In one embodiment, a total dose average power from 5 Watts to 10Watts may cause thermal coagulation. The first and second sequences ofelectrical pulses may be configured to reduce or eliminate thermalcoagulation at the electrode/tissue interface.

In certain embodiments, the polarity of the electric potentials coupledto the electrodes 24 a,b may be reversed during the electrical ablationtherapy. As shown in FIG. 9, the series of first pulse trains 70 maycomprise multiple biphasic pulse trains each having a positive firstpulse train amplitude +V₁ or a negative first pulse train amplitude −V₁,a first pulse train pulse width T_(w1), and a first pulse trainfrequency F₁, and the series of second pulse trains 72 may comprisemultiple biphasic pulse trains each having a positive second pulse trainamplitude +V₂ or a negative second pulse train amplitude −V₂, a secondpulse train pulse width T_(w2), and a second pulse train frequency F₂.The first pulses and the second pulses may be each independentlycharacterized by first and second amplitudes in the range of about ±100VDC to about ±10,000 VDC, first and second pulse widths in the range ofabout 1 μs to about 100 ms, and first and second frequencies in therange of about 1 Hz to about 10,000 Hz. In one embodiment, the firstsequence of electrical pulses and the second sequence of electricalpulses may comprise biphasic pulses. In one embodiment, the firstsequence of electrical pulses may comprise biphasic pulses and thesecond sequence of electrical pulses may not comprise biphasic pulses.In one embodiment, the first sequence of electrical pulses may notcomprise biphasic pulses and the second sequence of electrical pulsesmay comprise biphasic pulses.

As shown in FIGS. 10A-B, each of the first pulse trains may comprise aplurality of first pulses 70 a each having a positive first amplitude+v₁ or a negative first amplitude −v₁, a first pulse width t_(w1), and afirst frequency f₁, and each of the second pulse trains comprise aplurality of second pulses 72 a each having a positive second amplitude+v₂ or a negative second amplitude −v₂, a second pulse width t_(w2), anda second frequency f₂. In one embodiment, the first sequence ofelectrical pulses and the second sequence of electrical pulses maycomprise biphasic pulses. In one embodiment, the plurality of firstpulses may comprise biphasic pulses and the plurality of second pulsesmay not comprise biphasic pulses. In one embodiment, the plurality offirst pulses may not comprise biphasic pulses and the plurality ofsecond pulses may comprise biphasic pulses.

In one embodiment, the energy source 14 may be configured to generateand deliver DC first pulses and the second pulses at frequencies in therange of 1 Hz to 10,000 Hz, amplitudes in the range of ±100 VDC to ±3000VDC, and pulse width in the range of about 1 μs to about 100 ms. In oneembodiment, the first pulse trains may comprise a plurality of DC firstpulses having a positive polarity and an amplitude in the range of about+100 VDC to about +6000 VDC and a negative polarity and an amplitude inthe range of about −100 VDC to about −6000 VDC, the second pulse trainsmay comprise a plurality of second pulses having a positive polarity andan amplitude in the range of about +100 VDC to about +6000 VDC and anegative polarity and an amplitude in the range of about −100 VDC toabout −6000 VDC. In one embodiment, the method may comprise applying asequence of electrical pulses having a first polarity to induce cellthermal heating and applying a sequence of electrical pulses having anopposite polarity to induce cell necrosis by irreversibleelectroporation.

Without wishing to be bound to any particular theory, it is believedthat biphasic pulses may reduce the skeletal muscle contractions byreducing or eliminating the action potential caused by a positivemonophasic pulse. Biphasic pulses may reduce or eliminate skeletalmuscle contractions and cardiac events. A person skilled in the art willunderstand that poration of the cell membrane occurs when the pulseincreases the membrane voltage. A person skilled in the art may expectthe poration to be reversed by a negative going pulse. Without wishingto be bound to any particular theory, however, it is believed thathyperpolarization occurs on each side of the cell. For example, theopposite side of the cell membrane may be hyperpolarized when theelectric field switches orientation due to a negative-going pulse. Inother words, the polarization of the cell may be dependent on theorientation of the electric field.

According to certain embodiments, the method of treating tissue maycomprise heating the tissue by applying an electric field that is lessthan the necrotic threshold to lower the necrotic threshold beforeinducing cell necrosis. The method may comprise lowering the necroticthreshold by heating the tissue by applying an electric field that isless than about 700 V/cm, such as, for example, less than about 500 V/cmand less than about 300 V/cm. The method may comprise lowering thenecrotic threshold by 30% by heating the tissue by applying an electricfield that is less than about 700 V/cm. The method may comprise heatingthe tissue by applying an electric field that is less than the necroticthreshold to lower the necrotic threshold and inducing cell necrosis byirreversible electroporation by applying an electric filed that isgreater than or equal to the necrotic threshold. The method may compriseheating the tissue by applying an electric field that is less than 700V/cm to lower the necrotic threshold and inducing cell necrosis byirreversible electroporation by applying an electric filed that isgreater than about 700 V/cm.

According to certain embodiment, the method of treating tissue maycomprise applying a sequence of electrical pulses to increase a membranepotential to less than the necrotic threshold and applying a sequence ofelectrical pulses to increase a membrane potential to greater than orequal to the necrotic threshold. The method may comprise applying asequence of electrical pulses to increase a membrane potential from lessthan zero to greater than zero, applying a sequence of electrical pulsesto increase a membrane potential from greater than zero to less than thenecrotic threshold, and applying a sequence of electrical pulses toincrease a membrane potential from less than the necrotic threshold tothe necrotic threshold. The method may comprise applying a sequence ofelectrical pulses to increase a membrane potential from less than zeroto 100 mV, applying a sequence of electrical pulses to increase amembrane potential from 100 mV to 500 mV, and applying a sequence ofelectrical pulses to increase a membrane potential from 500 mV to thenecrotic threshold.

In one embodiment, the first sequence of electrical pulses may have apulse width of 50 μm or less and subsequent pulses may have highervoltages and pulse widths less than 50 μm. The pulses may increase themembrane potential from −70 mV to +100 mV, the next sequence of pulsesmay increase the membrane potential from 100 mV to 500 mV, and the finalsequence of pulses may have pulse width of 1 μs to increase the membranepotential to cause cell necrosis. Without wishing to be bound to anyparticular theory, it is believed that the synergistic effect ofapplying the first sequence of pulses to induce thermal heating andapplying the second sequence of pulses to induce cell necrosis byirreversible electroporation may decrease the membrane threshold from 1V to 0.7 V.

According to certain embodiments, the method may comprise forming apre-heated zone in the undesirable tissue by applying an electric fieldthat is less than the necrotic threshold. The method may compriseforming a pre-heated zone in the undesirable tissue by applying anelectric field that is less than the necrotic threshold and forming anecrotic zone by applying an electric field that is equal to or greaterthan the necrotic threshold to induce cell necrosis by irreversibleelectroporation. The method may comprise forming a pre-heated zone byapplying an electric field that is less than about 700 V/cm and forminga necrotic zone by applying an electric filed that is equal to orgreater than about 700 V/cm.

FIG. 11 is a graphical representation of a series of electrical pulsesthat may be applied to undesirable tissue. FIG. 11 illustrates therelationship between the pulse parameters and electrode temperature andthe size and proportion of the necrotic zone. As shown in FIG. 11, thesize and proportion of the necrotic zone may generally increase as thevoltage and/or temperature increases. The size and proportion of thenecrotic zone and thermal zone may be related to the pulse parameters,such as, for example, energy, peak power, and average power, andelectrode spacing. The contribution of voltage and temperature to thesize and proportion of the necrotic zone and thermal zone may be relatedto the peak pulsed power and average power.

In one embodiment, a pre-heated thermal zone may be formed in the tissueimmediately surrounding the electrodes 24 a,b at thetissue-electrode-interface by applying an electric field less than thenecrotic threshold. Without wishing to be bound to any particulartheory, it is believed that increasing the temperature of the tissue mayreduce the electric field necessary to cause cell necrosis in theundesirable tissue 48. Thus, the method of treating tissue may compriseapplying a combination of a series of first electrical pulses 70 havingsubstantially lower voltage (in the range of 1000 V to 2000 V) and aseries of second electrical pulses 72 having a higher voltage to inducecell necrosis. In one embodiment, a first series of pulses 70 may beapplied to create a pre-heated thermal zone to increase the temperatureof the tissue and then a second series of pulses 72 to induce cellnecrosis at a lower voltage then otherwise would be necessary withoutthe thermal heating of the tissue before inducing irreversibleelectroporation. In one embodiment, the method of treating tissue maycomprise applying a combination of a series of first electrical pulses70 having substantially lower voltage to increase the size of thepre-heated thermal zone at the same voltage.

Once positioned by the user, the electrodes may be energized to form apre-heated zone having a first shape in the tissue treatment region. Theshape of the pre-heated zone may be dependent on the position of thefirst and second electrodes. When the electrodes are re-energized, anecrotic zone having a second shape may be formed in the tissuetreatment region. The size of the pre-heated zone may be less than orequal to the size of the necrotic zone. This process may be repeated asoften as necessary to create any number of necrotic zones using theelectrical ablation apparatus. Various parameters, such as, for example,pressure, temperature, and duration, may be altered or adjustedaccording to the type of tissue in the tissue treatment region and thedesired size of the pre-heated zone and/or necrotic zone. In oneembodiment, the ablation apparatus may increase the size of the necroticzone relative to a similar ablation apparatus comprising a firstsequence of electrical pulses to induce cell necrosis in the tissue byirreversible electroporation. At anytime, the surgeon or clinician mayreposition the electrical ablation apparatus within the tissue treatmentregion and begin the process anew.

According to certain embodiments, the method of treating tissue maycomprise applying a first sequence of electrical pulses to inducethermal heating and applying a second sequence of electrical pulses toinduce cell necrosis by irreversible electroporation, wherein the firstand second sequences of electrical pulses create a ratio of thermalvolume to non-thermal volume of 5 to 1. The thermal volume may comprisethe volume of the pre-heated zone. In one embodiment, at least one ofthe first sequence of electrical pulses, the second sequence ofelectrical pulses, and sequence interval may be configured to create aratio of thermal volume to non-thermal volume of 2 to 1. In oneembodiment, at least one of the first sequence of electrical pulses, thesecond sequence of electrical pulses, and sequence interval may beconfigured to create a ratio of thermal zone volume to necrotic zonevolume of 1 to 1.

According to certain embodiments, the method may comprise measuring atleast one of temperature and pressure of the tissue treatment region.The method may comprise measuring at least one of temperature andpressure of the undesirable tissue. The method may comprise measuring atleast one of temperature and pressure adjacent at least one of the firstand second electrodes. The method may comprise measuring at least one oftemperature and pressure adjacent at least one of the first and secondelectrodes and applying a sequence of electrical pulses when at leastone of a predetermined temperature and a predetermined pressure isachieved. The method may comprise measuring at least one of temperatureand pressure adjacent at least one of the first and second electrodesand stopping a sequence of electrical pulses when at least one of apredetermined temperature and a predetermined pressure is achieved. Themethod may comprise measuring at least one of temperature and pressureadjacent at least one of the first and second electrodes and applying asequence of electrical pulses to achieve at least one of a predeterminedtemperature and a predetermined pressure.

Without wishing to be bound to any particular theory, it is believedthat the critical membrane voltage of a cell is inversely proportionalto the cell's temperature. In other words, the cell's critical membranevoltage may decrease as the cell's temperature increases. As a result, alower electric field may be applied to pre-heated undesirable tissue toinduce cell necrosis by irreversible electroporation than to the sameundesirable tissue without pre-heating. The predetermined temperaturemay be 40° C. to 50° C. For example, an electrical pulse or sequence ofelectrical pulses may be applied when the temperature of the tissuefalls below 50° C. The method may comprise stopping a sequence ofelectrical pulses when at least one of a predetermined temperature and apredetermined pressure is achieved. For example, an electrical pulse orsequence of electrical pulses may be stopped when the temperature of thetissue reaches 60° C. In one embodiment, the first and second sequencesof electrical pulses may be configured to maintain the tissue at atemperature sufficient to induce thermal coagulation. For example, thefirst and second sequences of electrical pulses may be configured tomaintain the tissue at a temperature between 50-60° C. The predeterminedpressure may be atmospheric pressure.

According to certain embodiments, the ablation apparatus may reduce therisk of an electrical arc relative to a similar ablation apparatuscomprising a first sequence of electrical pulses to induce cell necrosisin the tissue by irreversible electroporation. Under certain conditions,an arc may form between the two electrodes. For example, high voltagemay cause a breakdown in air in the space between the un-insulatedconductive portions of the electrodes that are not fully embedded in thetissue. An electrical arc at high voltages (>10 k VDC) may occur whenthe un-insulated conductive portions of the two electrodes are not fullyembedded into the tissue or the tissue moves away from the electrode tipand the high voltage causes an electrical breakdown of the gassurrounding the electrode tip. The first and second sequences ofelectrical pulses may be configured to reduce or eliminate the creationof an arc. As described in commonly owned U.S. patent application Ser.No. 12/651,181, a gel may be continuously supplied to the space todisplace the air in the space and prevent an arc from forming. The gelmay be any water-based, water-soluble lubricant, such as, for example,KY® Jelly available from Johnson & Johnson.

FIG. 12 illustrates one embodiment of the electrical ablation system 10shown in FIG. 1 in use to treat undesirable tissue 48 located on thesurface of the liver 50. The undesirable tissue 48 may be representativeof diseased tissue, cancer, malignant and benign tumors, masses,lesions, and other abnormal tissue growths. In use, the electricalablation device 20 may be introduced into or proximate the tissuetreatment region through a port 52 of a trocar 54. The trocar 54 may beintroduced into the patient via a small incision 59 formed in the skin56. The endoscope 12 may be introduced into the patient trans-anallythrough the colon, trans-orally down the esophagus and through thestomach using translumenal techniques, or through a small incision orkeyhole formed through the patient's abdominal wall (e.g., theperitoneal wall). The endoscope 12 may be employed to guide and locatethe distal end of the electrical ablation device 20 into or proximatethe undesirable tissue 48. Prior to introducing the flexible shaft 22through the trocar 54, the sheath 26 may be slid over the flexible shaft22 in a direction toward the distal end thereof to cover the electrodes24 a,b until the distal end of the electrical ablation device 20 reachesthe undesirable tissue 48.

Once the electrical ablation device 20 has been suitably introduced intoor proximate the undesirable tissue 48, the sheath 26 may be retractedto expose the electrodes 24 a,b to treat the undesirable tissue 48. Thetreat the undesirable tissue 48, the operator initially may locate thefirst electrode 24 a at a first position and the second electrode 24 bat a second position using endoscopic visualization and maintaining theundesirable tissue 48 within the field of view of the flexible endoscope12. The first position may be near a perimeter edge of the undesirabletissue 48. Once the electrodes 24 a,b are located into or proximate theundesirable tissue 48, the electrodes 24 a,b may be energized with afirst sequence of electrical pulses to deliver a first energy dose thatis less than the necrotic threshold to induce thermal heating in thetissue surrounding the electrode/tissue interface. Once the temperatureand/or pressure of the undesirable tissue 48 achieves a predeterminedthreshold, the electrodes 24 a,b may be energized with a second sequenceof electrical pulses to deliver a second energy dose equal to or greaterthan the necrotic threshold to induce cell necrosis in the tissue byirreversible electroporation to create a necrotic zone 65. For example,once the first and second electrodes 24 a,b are located in the desiredpositions, the undesirable tissue 48 may be exposed to an electric fieldgenerated by energizing the first and second electrodes 24 a,b with theenergy source 14.

The electric field created by the first sequence of electrical pulsesmay have a magnitude, frequency, pulse width suitable to increase thetemperature of the undesirable tissue to a predetermined threshold. Theelectric field created by the second sequence of electrical pulses mayhave a magnitude, frequency, and pulse width suitable to induceirreversible electroporation in the undesirable tissue 48 within thenecrotic zone 65. Without wishing to be bound to any particular theory,it is believed that increasing the temperature of the undesirable tissueto a predetermined threshold may reduce the magnitude, frequency, and/orpulse width of the electric field suitable to induce irreversibleelectroporation in the undesirable tissue 48. The size of the necroticzone may be substantially dependent on the size and separation of theelectrodes 24 a,b. The treatment time may be defined as the time thatthe electrodes 24 a,b are activated or energized to generate theelectric pulses suitable for inducing thermal heating and/orirreversible electroporation in the undesirable tissue 48.

This procedure may be repeated to destroy relatively larger portions ofthe undesirable tissue 48. At anytime, the surgeon or clinician mayreposition the first and second electrodes 24 a,b and begin the processanew. In other embodiments, the electrical ablation device may comprisemultiple needle electrodes that may be employed to treat the undesirabletissue 48. Those skilled in the art will appreciate that similartechniques may be employed to ablate any other undesirable tissues thatmay be accessible trans-anally through the colon, and/or orally throughthe esophagus and the stomach using translumenal access techniques.

The embodiments of the electrical ablation devices described herein maybe introduced inside a patient using minimally invasive or open surgicaltechniques. In some instances it may be advantageous to introduce theelectrical ablation devices inside the patient using a combination ofminimally invasive and open surgical techniques. Minimally invasivetechniques may provide more accurate and effective access to thetreatment region for diagnostic and treatment procedures. To reachinternal treatment regions within the patient, the electrical ablationdevices described herein may be inserted through natural openings of thebody such as the mouth, anus, and/or vagina, for example. Minimallyinvasive procedures performed by the introduction of various medicaldevices into the patient through a natural opening of the patient areknown in the art as NOTES™ procedures. Surgical devices, such as anelectrical ablation devices, may be introduced to the treatment regionthrough the channels of the endoscope to perform key surgical activities(KSA), including, for example, electrical ablation of tissues usingirreversible electroporation energy. Some portions of the electricalablation devices may be introduced to the tissue treatment regionpercutaneously or through small-keyhole-incisions.

Endoscopic minimally invasive surgical and diagnostic medical proceduresare used to evaluate and treat internal organs by inserting a small tubeinto the body. The endoscope may have a rigid or a flexible tube. Aflexible endoscope may be introduced either through a natural bodyopening (e.g., mouth, anus, and/or vagina). A rigid endoscope may beintroduced via trocar through a relatively small-keyhole-incisionincisions (usually 0.5 cm to 1.5 cm). The endoscope can be used toobserve surface conditions of internal organs, including abnormal ordiseased tissue such as lesions and other surface conditions and captureimages for visual inspection and photography. The endoscope may beadapted and configured with channels for introducing medical instrumentsto the treatment region for taking biopsies, retrieving foreign objects,and/or performing surgical procedures.

Once an electrical ablation device is inserted in the human bodyinternal organs may be reached using trans-organ or translumenalsurgical procedures. The electrical ablation device may be advanced tothe treatment site using endoscopic translumenal access techniques toperforate a lumen, and then, advance the electrical ablation device andthe endoscope into the peritoneal cavity. Translumenal access proceduresfor perforating a lumen wall, inserting, and advancing an endoscopetherethrough, and pneumoperitoneum devices for insufflating theperitoneal cavity and closing or suturing the perforated lumen wall arewell known. During a translumenal access procedure, a puncture must beformed in the stomach wall or in the gastrointestinal tract to accessthe peritoneal cavity. One device often used to form such a puncture isa needle knife which is inserted through the channel of the endoscope,and which utilizes energy to penetrate through the tissue. A guidewireis then feed through the endoscope and is passed through the puncture inthe stomach wall and into the peritoneal cavity. The needle knife isremoved, leaving the guidewire as a placeholder. A balloon catheter isthen passed over the guidewire and through the channel of the endoscopeto position the balloon within the opening in the stomach wall. Theballoon can then be inflated to increase the size of the opening,thereby enabling the endoscope to push against the rear of the balloonand to be feed through the opening and into the peritoneal cavity. Oncethe endoscope is positioned within the peritoneal cavity, numerousprocedures can be performed through the channel of the endoscope.

The endoscope may be connected to a video camera (single chip ormultiple chips) and may be attached to a fiber-optic cable systemconnected to a “cold” light source (halogen or xenon), to illuminate theoperative field. The video camera provides a direct line-of-sight viewof the treatment region. If working in the abdomen, the abdomen may beinsufflated with carbon dioxide (CO₂) gas to create a working andviewing space. The abdomen is essentially blown up like a balloon(insufflated), elevating the abdominal wall above the internal organslike a dome. CO₂ gas is used because it is common to the human body andcan be removed by the respiratory system if it is absorbed throughtissue.

Once the electrical ablation devices are located at the target site, thediseased tissue may be electrically ablated or destroyed using thevarious embodiments of electrodes discussed herein. The placement andlocation of the electrodes can be important for effective and efficientelectrical ablation therapy. For example, the electrodes may bepositioned proximal to a treatment region (e.g., target site orworksite) either endoscopically or transcutaneously (percutaneously). Insome implementations, it may be necessary to introduce the electrodesinside the patient using a combination of endoscopic, transcutaneous,and/or open techniques. The electrodes may be introduced to the tissuetreatment region through a channel of the endoscope, an overtube, or atrocar and, in some implementations, may be introduced throughpercutaneously or through small-keyhole-incisions.

Preferably, the various embodiments of the devices described herein willbe processed before surgery. First, a new or used instrument is obtainedand if necessary cleaned. The instrument can then be sterilized. In onesterilization technique, the instrument is placed in a closed and sealedcontainer, such as a plastic or TYVEK® bag. The container and instrumentare then placed in a field of radiation that can penetrate thecontainer, such as gamma radiation, x-rays, or high-energy electrons.The radiation kills bacteria on the instrument and in the container. Thesterilized instrument can then be stored in the sterile container. Thesealed container keeps the instrument sterile until it is opened in themedical facility.

It is preferred that the device is sterilized prior to use. This can bedone by any number of ways known to those skilled in the art includingbeta or gamma radiation, ethylene oxide, steam.

The various embodiments described herein may be better understood whenread in conjunction with the following representative examples. Thefollowing examples are included for purposes of illustration and notlimitation.

An ablation apparatus comprising two electrodes coupled to a energysource and a temperature sensor according to certain embodiments wasused to deliver a series of electrical pulses ex vivo to healthy porcineliver to induce irreversible electroporation (Dose 1). In oneembodiment, the Dose 1 pulse parameters may include a 3,000 V amplitude,a 10 μs pulse width, 10 total number of pulses per burst, a frequency of200 Hz, 6 total number of bursts, and a 3 s delay between each burst.Dose 1 is generally characterized by low energy and high voltage. Dose 1was not suitable for synchronizing to a patient's cardiac cycle. FIG. 13is a photograph of the porcine liver after receiving Dose 1. Thenecrotic zone 100 is generally indicated by the discoloration of thetissue. The temperature was monitored using the temperature sensorillustrated in FIG. 4. FIG. 14 is a graphical representation oftemperature during Dose 1. Without wishing to be bound to any particulartheory, it is believed that temperature is related to the distancebetween the electrodes. As shown in FIG. 14, an electrode spacing of 1.5cm generated a maximum temperature of about 51° C. at the positiveelectrode and an electrode spacing of 1.0 cm generated a maximumtemperature of about 59° C. at the positive electrode. As shown in FIG.14, the temperature increases as the distance between the electrodesdecreases.

FIGS. 15A-D include photographs of porcine liver after receiving aseries of electrical pulses having an amplitude of 3 kV that may beapplied to undesirable tissue to induce irreversible electroporation.FIG. 15A is a photograph of porcine liver after receiving a firstsequence of electrical pulses. FIG. 15B is a photograph of the porcineliver after receiving the second sequence of electrical pulses. Thetemperature of the porcine tissue after the second sequence ofelectrical pulses was 40° C. FIG. 15C is a photograph of the porcineliver after receiving the third sequence of electrical pulses. Thetemperature of the porcine tissue after the third sequence of electricalpulses was 37° C. FIG. 15D is a photograph of the porcine liver afterreceiving the fourth sequence of electrical pulses. The temperature ofthe porcine tissue after the fourth sequence of electrical pulses was45° C. The necrotic zone caused by each sequence of electrical pulses isgenerally indicated by the discoloration of the tissue. The sequenceinterval between each series of electrical pulses was 5 seconds. Thetotal dose time was 20 seconds.

An ablation apparatus comprising two electrodes coupled to a energysource and a temperature sensor according to certain embodiments wasused to deliver a series of electrical pulses ex vivo to healthy porcineliver to induce irreversible electroporation (Dose 2). In oneembodiment, the Dose 2 parameters may include a first series of burstsincluding a 1000 V amplitude, a 5 μs pulse width, 500 total number ofpulses per burst, a total of 30 first series bursts, a 0.1 s delaybetween each burst followed by a second series of bursts pulsesincluding a 1500 V amplitude, a 5 μs pulse width, 500 total number ofpulses per burst, a total of 20 second bursts, a 0.1 s delay betweeneach burst followed by a third series of bursts including a 3000 Vamplitude, a 10 μs pulse width, 10 total number of pulses per burst, atotal of 10 third series bursts, a 3 s delay between each burst. Thefrequency may be 200 Hz. Dose 2 is generally characterized by amulti-train dose at a higher energy than Dose 1. Dose 2 was not suitablefor synchronizing to a patient's cardiac cycle. As shown in FIG. 16, thefirst pulse train included 500 pulses per burst at a pulse width of 5μs, a frequency of 200 Hz, and an amplitude of 1 kV, the second pulsetrain included 500 pulses per burst at a pulse width of 5 μs, afrequency of 200 Hz, and an amplitude of 1.5 kV, and the third pulsetrain included 10 pulses per burst at a pulse width of 10 μs, afrequency of 200 Hz, and an amplitude of 3 kV.

The size and area of the necrotic zone of Dose 1 was compared to thesize and area of the necrotic zone of Dose 2. FIG. 17 is a graphillustrating the average area of the necrotic zone for Dose 1 and theaverage area of the necrotic zone for Dose 2. As shown in FIG. 17, Dose1 exhibited a smaller average area of the necrotic zone than Dose 2.FIG. 18A is a graph illustrating the average area of the necrotic zonefor Dose 1 and the average area of the necrotic zone for Doses 2 a,b. Asshown in FIG. 18A, the average necrotic zone dimensions and area forDose 1 was 1 cm×2.5 cm and 2.5 cm², respectively. The average necroticzone dimensions and area for Dose 2 was 2.0 cm×3.67 cm and 7.34 cm²,respectively. FIG. 18B includes photographs of the necrotic zoneproduced by Doses 1, 2 a, and 2 b. As shown in FIGS. 17 and 18, the sizeand area of the necrotic zone generally increases as the energyincreases.

FIG. 19 is a graphical representation of a series of electrical pulsesthat may be delivered to undesirable tissue to induce irreversibleelectroporation. The multi-train electrical sequence may be synchronizedwith a patient's cardiac cycle. As shown in FIG. 19, the pulse train mayinclude up to 180 pulses per burst at a pulse width of 10 μs, afrequency of 200 Hz, and an amplitude of 3 kV. The total burst time ofeach burst may fit within the latent period, or the period of electricalinactivity of the cardiac cycle. The latent period may also be known asthe refractory period. The temperature may be measured between eachburst. In one embodiment, the pulse parameters and maximum temperaturemay be adjusted to achieve a non-thermal zone of cell death (“IREDose”). The IRE Dose may include a maximum temperature of 50° C. and atypical sequence time of about 1 minute. In one embodiment, for example,the IRE Dose parameters may include a 3,000 V amplitude, a 10 μs pulsewidth, 15 total number of pulses per burst, frequency of each 10 μspulse within the bursts of 200 Hz, a 3 s delay between each burst, and20 total number of bursts. The IRE Dose may be characterized by no orreduced thermal damage to the tissue surrounding the electrode. In oneembodiment, the pulse parameters and maximum temperature may be adjustedto slowly increase the temperature of the tissue (“IRE+ Dose”). The IRE+Dose may increase the temperature of a large volume of tissue by a fewdegrees, such as, for example, 0-10° C. and 1-5° C., over a relativelylonger period of time. The IRE+ Dose may include a typical sequence timeof about 8 minutes. For example, the IRE+ Dose parameters may include a3,000 V amplitude, a 10 μs pulse width, 20 total number of pulses perburst, frequency of each 10 μs pulse within the bursts of 200 Hz, a 3 sdelay between each burst, and 90 total number of bursts at a maximumtemperature of 60° C. The electrode spacing may be 2 cm. The IRE+ Dosemay be characterized by a large necrosis zone. In one embodiment, thepulse parameters and maximum temperature may be adjusted to rapidlyincrease the temperature of the tissue (“IRE+Heat Dose”). The IRE+HeatDose may increase the temperature of a large volume of tissue by a fewdegrees, such as, for example, 0-10° C. and 1-5° C., over a relativelyshorter period of time. The IRE+Heat Dose may include a typical sequencetime of about 4 minutes. In one embodiment, for example, the IRE+HeatDose parameters may include a 3,000 V amplitude, a 10 μs pulse width, 20total number of pulses per burst, frequency of each 10 μs pulse withinthe bursts of 200 Hz, a 0.1 s delay between each burst, and 90 totalnumber of bursts at a maximum temperature of 60° C. The highertemperature in the tissue surrounding the electrodes may cause thermalcoagulation. Without wishing to be bound to any particular theory, it isbelieved that thermal coagulation may occur at a higher average powerand same energy. The IRE+Heat Dose may be characterized by a largernecrotic zone than the IRE Dose and a shorter time than the IRE+ Dose.

FIGS. 20A-C are photographs of a healthy porcine liver after receivingthe IRE Dose, IRE+ Dose, and IRE+Heat Dose, respectively. As shown inthe FIG. 20A, the IRE Dose has a necrotic zone having a size of 1.2cm×2.3 cm and an area of 2.76 cm². As shown in the FIG. 20B, the IRE+Dose has a necrotic zone having a size of 2.1 cm×3.7 cm and an area of7.77 cm². As shown in the FIG. 20C, the IRE+Heat Dose has a necroticzone having a size of 1.6 cm×3.6 cm and an area of 5.76 cm². TheIRE+Heat Dose has a thermal zone located within the necrotic zone. Thesize and area of the thermal zone (lighter area) is smaller than thesize and area of the necrotic zone.

FIG. 21 is a graphical representation of the electrode temperatureduring the IRE Dose having a maximum temperature limit of 50° C. Asshown in FIG. 21, the maximum temperature at the positive electrode wasabout 47° C. at 69 seconds. FIG. 22 is a graphical representation of thetemperature during the IRE+ Dose having a maximum temperature limit of90° C. As shown in FIG. 22, the maximum temperature at the positiveelectrode was about 62° C. at about 430 seconds. FIG. 23 is a graphicalrepresentation of the temperature during the IRE+Heat Dose having amaximum temperature limit of 90° C. As shown in FIG. 23, the maximumtemperature at the positive electrode was about 88° C. at about 220seconds. FIG. 24 is a graphical representation of the temperature duringthe IRE+Heat Dose having a maximum temperature limit of 90° C. As shownin FIG. 24, the maximum temperature at the positive electrode was about96° C. at about 259 seconds.

The size and proportion of the necrosis zone may be also related toelectrode spacing. FIGS. 25A-C include photographs of healthy porcineliver after receiving an IRE Dose having an electrode spacing of 1.5 cm,an IRE+ Dose having an electrode spacing of 2.0 cm, an IRE+Heat Dosehaving an electrode spacing of 2.0 cm. As shown in FIGS. 25A-C, the IRE+Dose has the largest necrotic zone and the IRE Dose has the smallestnecrotic zone. The IRE+Heat Dose has a necrotic zone intermediate theIRE Dose and IRE+ Dose. The IRE+Heat Dose has a thermal zone (lighterarea) is smaller than the necrotic zone.

FIGS. 26A-F are graphical representations of simulated necrotic zones(white) and thermal zones (gray) of porcine livers (black) afterreceiving a series of electrical pulses that may be applied toundesirable tissue to induce irreversible electroporation according tocertain embodiments described herein. FIGS. 26A,B include computersimulation of an IRE Dose having an electrode spacing of 1.5 cm and 2.0cm, respectively. A necrotic zone of 2.3 cm×1.02 cm is predicted for anIRE Dose having an electrode spacing of 1.5 cm. A necrotic zone of 2.8cm wide is predicted for an IRE Dose having an electrode spacing of 2.0cm. FIGS. 26C,D include computer simulation of an IRE+ Dose having anelectrode spacing of 1.5 cm and 2.0 cm, respectively. A necrotic zone of3.4 cm×2.09 cm is predicted for an IRE+ Dose having an electrode spacingof 2.0 cm and a 400 V/cm threshold. A necrotic zone of 2.92 cm×2.04 cmis predicted for an IRE+ Dose having an electrode spacing of 1.5 cm anda 400 V/cm threshold. Without wishing to be bound to any particulartheory, it is believed that decreasing the necrotic threshold mayincrease the size of the necrotic zone. As shown in FIGS. 26A,C, thesize of the necrotic zone in FIG. 26A is smaller than the size of thenecrotic zone in FIG. 26C. FIGS. 26E,F include computer simulation of anIRE+Heat Dose having an electrode spacing of 2.0 cm and 3.0 cm,respectively. As shown in FIG. 26E, an IRE+Heat Dose having an electrodespacing of 2.0 cm produces a thermal zone (gray region). The width ofthe necrotic zone of an IRE+Heat Dose having an electrode spacing of 2.0cm is less than the width of the necrotic zone of an IRE+ Dose having anelectrode spacing of 2.0 cm. As shown in FIG. 26F, an IRE+Heat Dosehaving an electrode spacing of 3.0 cm produces thermal zones around eachelectrode. The width of the necrotic zone of an IRE+Heat Dose having anelectrode spacing of 3.0 cm is less than the width of the necrotic zoneof an IRE+Heat Dose having an electrode spacing of 2.0 cm. Withoutwishing to be bound to any particular theory, it is believed that theratio of the necrotic zone length and necrotic zone width generallycorresponds to the electric field pattern. The electric field patterngenerally becomes long and narrow as the electrode spacing increases.

According to certain embodiments, the electrical ablation system may beconfigured to treat larger masses of tissue. As described above, theablation apparatus may generally comprise a one or more electrodes, suchas, for example, two, three, four, and five electrodes, configured to bepositioned into or proximal to undesirable tissue in a tissue treatmentregion. The ablation apparatus may comprise a central electrode and anelectrode array comprising a plurality of electrodes. The electrodes maybe coupled to an energy source operative to independently generate anddeliver a first sequence of electrical pulses to the electrode array anda second sequence of electrical pulses to the central electrode. Thefirst sequence of electrical pulses to the electrode array may deliver afirst energy dose that is less than the necrotic threshold to inducethermal heating in the tissue. The second sequence of electrical pulsesto the central electrode may deliver a second energy dose equal to orgreater than the necrotic threshold to induce cell necrosis in thetissue. In certain embodiments, the electrode array and centralelectrode may induce thermal heating and/or cell necrosis in largermasses of tissue relative to conventional electrical ablation therapies.

In various embodiments, the electrode array and central electrode mayreduce the pain, trauma, and/or hemorrhaging associated with treatinglarger masses of undesirable tissue relative to conventional electricalablation therapies. For example, in various embodiments, the electrodearray may spread the heating more rapidly than conventional electricalablation therapies by creating multiple heat sources. The surgeon orclinician may not need to reposition the electrical ablation apparatuswithin the tissue treatment region to treat large masses of undesirabletissue. Further, the relative positions and orientations of electrodearray and central electrode may induce thermal heating and/or cellnecrosis in larger masses of tissue of various shapes and sizes relativeto conventional electrical ablation therapies.

In certain embodiments, an electrical ablation system may comprise anelectrical ablation device comprising a relatively flexible member orshaft that may be introduced to the tissue treatment region using any ofthe techniques discussed above, such as, for example, an open incisionand a trocar, through one or more of the channels of an endoscope,percutaneously, or transcuteously. The electrical ablation system maycomprise an electrical ablation device comprising a central electrodeand an electrode array. Referring to FIG. 27, in one embodiment, thecentral electrode 124 a and the electrode array comprising a pluralityof electrodes 124 b may extend out from the distal end of the shaft 122of the electrical ablation device. A sheath 126 may be slid over theflexible shaft 122. One or more of the plurality of electrodes of theelectrode array and central electrode may be adapted and configured toslideably move in and out of a cannula, lumen, or channel formed with aflexible shaft, a working channel formed within a flexible shaft of theendoscope, or may be independently located independently of theendoscope. As described above, one or more of the electrodes may befixed in place or provide a pivot about which other electrode(s) may bemoved to other points in the tissue treatment region. As shown in FIG.27, in a deployed state, an electrical ablation system comprising acentral electrode 124 a and the electrode array comprising a pluralityof electrodes 124 b may engage a greater area than an electricalablation system comprising two electrodes.

When the electrode array and/or central electrode is positioned at thedesired location into or proximate the tissue treatment region, theelectrodes may be connected to or disconnected from the energy source byactuating or de-actuating an activation switch on the hand piece. Theelectrode array and central electrode may deliver electric field pulsesto the undesirable tissue. As described above, the electrical fieldpulses may be characterized by various parameters, such as, for example,pulse shape, amplitude, frequency, pulse width, polarity, total numberof pulses and duration. The electric field pulses delivered by theelectrode array may be sufficient to induce thermal heating in theundesirable tissue without inducing irreversible electroporation in theundesirable tissue. The electric field pulses delivered by the centralelectrode may be sufficient to induce irreversible electroporation inthe undesirable tissue. A ground pad may be positioned proximal to thetissue. A ground pad may be positioned adjacent to the tissue. Theground pad may serve as a return path for current from the generatorthrough the electrodes.

In certain embodiments, the ablation system may comprise an energysource, as discussed above. The electrode array and central electrodemay be coupled to the energy source. Once the energy source is coupledthe electrode array and central electrode, an electric field may beindependently formed at a distal end of one or more of the electrodes.The energy source may be configured to produce electrical energysuitable for thermal heating and/or electrical ablation. The energysource may be configured to independently produce electrical waveforms,such as, for example, RF waveforms, microwave waveforms, and/orultrasonic waveforms, at predetermined frequencies, amplitudes, pulsewidths and/or polarities suitable for thermal heating by the electrodearray and electrical ablation by the central electrode. The energysource may be configured to produce destabilizing electrical potentials(e.g., fields) suitable to induce thermal heating by the electrode arrayand electrical ablation by the central electrode. The energy source maybe configured to deliver electrical pulses in the form of DC and/or ACvoltage potentials to the electrodes. As described above, a timingcircuit may be coupled to the output of the energy source to generateelectric pulses. As discussed above, the energy source may be configuredto operate in either biphasic mode or monophasic mode. The energy sourcemay comprise the controller.

In certain embodiments, the ablation system may comprise at least onecontroller configured to concurrently or sequentially operate the energysource. The controller may comprise a processor (e.g., amicroprocessor), a central processing unit (CPU), a digital signalprocessor (DSP), an application-specific integrated circuit (ASIC), afield programmable gate array (FPGA) and any combinations thereof. Thecontroller may comprise digital and/or analog circuit elements andelectronics. In one embodiment, the controller may be configured toautomatically control at least one parameter associated with thedelivery of the electrical pulse. In one embodiment, the controller maybe operably coupled to the energy source and configured to control atleast one parameter associated with the delivery of the electricalpulse.

Referring to FIG. 28A, in certain embodiments, an electrical ablationsystem may comprise a controller 110 comprising a processor 105 and amemory 120. The controller 110 may comprise an analog-to-digitalconverter 125, an amplifier 130, and/or a pulse width modulator (notshown). The processor may be communicably coupled to the energy source(not shown) and configured to control at least one parameter associatedwith the delivery of the electrical pulse. The controller may executeinstructions to implement the electrical ablation system. The electricalablation system may comprise a general purpose computer 135 operablycoupled to the controller 110 and programmed to control the controller110.

Referring to FIG. 28B, in certain embodiments, an electrical ablationsystem may comprise a digital processing system 210. The digitalprocessing system 210 may comprise a processor 205 and a memory 220. Thedigital processing system 210 may comprise an amplifier 230. The digitalprocessing system 210 may comprise one or more embedded applicationsimplemented as firmware, software, hardware, and any combinationthereof. The digital processing system 210 may comprise variousexecutable modules and/or blocks, such as, for example, software,programs, data, drivers, and application program interfaces. The digitalprocessing system 210 may be communicably coupled to the energy source(not shown) and configured to control at least one parameter associatedwith the delivery of the electrical pulse. The digital processing system210 may execute instructions to implement the electrical ablationsystem. The electrical ablation system may comprise a general purposecomputer 235 operably coupled to the digital processing system 210 andprogrammed to control the digital processing system 210.

Referring to FIG. 28C, in certain embodiments, an electrical ablationsystem may comprise a controller 310 comprising an AC voltage source305. The controller 310 may comprise an amplifier 330. The controller310 may be communicably coupled to the energy source (not shown) andconfigured to control at least one parameter associated with thedelivery of the electrical pulse. The controller 310 may executeinstructions to implement the electrical ablation system. The electricalablation system may comprise a general purpose computer 335 operablycoupled to the controller 310 and programmed to control the controller310.

In various embodiments, the controller and components thereof, such asthe processor and memory, may comprise more than one separate functionalelement, such as various modules and/or blocks. Although certain modulesand/or blocks may be described by way of example, it will be appreciatedthat a greater or lesser number of modules and/or blocks may be used andstill fall within the scope of the embodiments. Further, althoughvarious embodiments may be described in terms of modules and/or blocksto facilitate the desired function, such modules and/or blocks may beimplemented by one or more hardware components, e.g., processor, ComplexProgrammable Logic Device (CPLD), Digital Signal Processor (DSP),Programmable Logic Devices (PLD), Application Specific IntegratedCircuit (ASIC), circuits, registers and/or software components, e.g.,programs, subroutines, logic and/or combinations of hardware andsoftware components.

In certain embodiments, an electrical ablation system may comprise oneor more memories that, for example, store instructions or data, forexample, volatile memory (e.g., Random Access Memory (RAM), DynamicRandom Access Memory (DRAM), or the like), non-volatile memory (e.g.,Read-Only Memory (ROM), Electrically Erasable Programmable Read-OnlyMemory (EEPROM), Compact Disc Read-Only Memory (CD-ROM), or the like),persistent memory, or the like. Further non-limiting examples of one ormore memories include Erasable Programmable Read-Only Memory (EPROM),flash memory, and the like. The one or more memories may be coupled to,for example, one or more controllers by one or more instruction, data,or power buses.

According to certain embodiments, a computer-implemented system fordelivering energy to tissue having a necrotic threshold may generallycomprise an electrode array comprising a plurality of electrodes, acentral electrode, a ground pad, a processor, and a memory coupled tothe processor and storing instructions to be executed by the processorto apply a first sequence of electrical pulses to the electrode arrayless than the necrotic threshold to induce thermal heating in thetissue, apply a second sequence of electrical pulses to the centralelectrode equal to or greater than the necrotic threshold to induce cellnecrosis in the tissue by irreversible electroporation, and apply aground potential to the ground pad. The ground pad may be adjacent tothe tissue. The ground pad me be proximal to the tissue.

FIG. 27 shows one embodiment of an electrical ablation system afterdeploying the electrode array and central electrode. Each of theplurality of electrodes 124 b may be spaced apart from the other of theplurality of electrodes 124 b. The central electrode 124 a may bepositioned intermediate the plurality of electrodes 124 b. The centralelectrode 124 a may be centrally positioned intermediate the pluralityof electrodes 124 b. In various embodiments, the central electrode 124 amay be aligned with the sheath 126. In other embodiments, the centralelectrode 124 a may not be aligned with the sheath 126. In variousembodiments, the distance from one or more of the plurality ofelectrodes 124 b to the central electrode 124 a may be from 0.1 cm to 5cm, such as, for example, 1 cm, 1.5 cm, 2 cm, and 3 cm. In variousembodiments, the distance from one or more of the plurality ofelectrodes 124 b to one or more of the other of the plurality ofelectrodes 124 b may be from 0.1 cm to 5 cm, such as, for example, 1 cm,1.5 cm, 2 cm, and 3 cm. In various embodiments, the plurality ofelectrodes 124 b of the electrode array may comprise outer electrodesand the central electrode 124 a may comprise an inner electrode. Theouter electrodes may surround the inner electrode. Each of theelectrodes 124 a,b may be spaced apart from the ground pad (not shown).In one embodiment, the ground pad may be replaced by one or more of theelectrodes 124 a,b.

In certain embodiments, the system may comprise an energy source coupledto the electrode array and the central electrode operative to generateand deliver the first sequence of electrical pulses and the secondsequence of electrical pulses to tissue having a necrotic threshold. Theelectrode array and the central electrode may be independently adaptedand configured to electrically couple to the energy source (e.g.,generator, waveform generator). The energy source may comprise any ofthe energy sources described herein. The energy source may be configuredto generate DC electric pulses at frequencies in the range of about 1 Hzto about 10,000 Hz, amplitudes in the range of about ±100 VDC to about±6,000 VDC, and pulse width in the range of about 1 μs to about 100 ms.The energy source may be configured to generate electric pulses suitableto induce thermal heating and irreversible electroporation in thetissue. The energy source may be operated in biphasic mode andmonophasic mode.

In certain embodiments, the system may comprise a controller, such as,for example, any of the controllers illustrated in FIGS. 28A-C. Thecontroller may be coupled to the energy source and configured to controlat least one parameter associated with the delivery of the electricalpulses. The at least one parameter may comprise frequency, amplitude,pulse width, polarity, voltage, total number of pulses, and delaybetween pulses bursts. For example, the controller may produce a seriesof m electric pulses of sufficient amplitude and duration less than thenecrotic threshold to induce thermal heating in the tissue when melectric pulses are applied to the electrode array, and a series of nelectric pulses of sufficient amplitude and duration to induceirreversible electroporation suitable for tissue ablation when nelectric pulses are applied to the central electrode. In one embodiment,the energy source may comprise the controller.

In certain embodiments, the system may comprise instructions to beexecuted by the processor to deliver a first sequence of electricalpulses sufficient to create a thermal zone in a first portion of thetissue induced by thermal heating in an area near anelectrode-tissue-interface of each of the plurality of electrodes of theelectrode array, and a second sequence of electrical pulses sufficientto create a necrotic zone in a second portion of tissue induced byirreversible electroporation in an area surrounding both the centralelectrode and the plurality of electrodes of the electrode array.Referring to FIG. 29A, the first sequence of electrical pulses maycreate a thermal zone 500 in an area near the electrode-tissue-interfaceof one or more of the plurality of electrodes 524 b of the electrodearray. As shown in FIG. 29A, the plurality of electrodes 524 b of theelectrode array may comprise outer electrodes and the central electrode524 a may comprise an inner electrode aligned with the sheath 526. Thecurrent flowing from the outer electrodes 524 b to the ground pad (i.e.,return pad) may induce thermal heating in the tissue near the electrodes524 b. The thermal zone 500 of one of the electrodes 524 b may notcontact the thermal zone 500 of the other electrodes 524 b. As shown inFIG. 29A, a thermal zone may not be created in an area near theelectrode-tissue-interface of the central electrode 524 a. In oneembodiment, the system may comprise instructions to be executed by theprocessor to not deliver a sequence of electrical pulses to the centralelectrode to induce thermal heating when the electrical pulses aredelivered to the electrode array. In one embodiment, the system maycomprise instructions to be executed by the processor to deliver thefirst sequence of electrical pulses to the central electrode when theelectrical pulses are delivered to the electrode array.

As shown in FIG. 29B, after a period of time, the thermal zone 500 ofone or more of the electrodes 524 b may contact the other electrodes 524b. In one embodiment, the thermal zone 500 of one or more of theelectrodes 524 b may contact the thermal zone 500 of one or more of theother electrodes 524 b. The volume of the thermal zone 500 for one ormore of the electrodes 524 b may be from 1 cm³ to 10 cm³, 2 cm³ to 8cm³, and 4 cm³ to 6 cm³. The total volume of the thermal zone 500 (i.e.,the sum of each thermal zone) may be from 1 cm³ to 50 cm³, 4 cm³ to 25cm³, and 10 cm³ to 20 cm³. The thermal zone 500 of one or more of theelectrodes 524 b may contact the central electrode 524 a. The centralelectrode 524 a may be positioned within the thermal zone 500. Referringto FIG. 29B, the central electrode 524 a may be positioned into thetissue 501 outside the thermal zones 500. In certain embodiments, thecentral electrode 524 a may be positioned into the tissue 501 within thethermal zone 500 even though the central electrode 524 a did not inducethe thermal zone 500. In various embodiments, the central electrode 524a may be positioned prior to forming the thermal zones 500 or afterforming the thermal zones 500. The system may comprise instructions tobe executed by the processor to not deliver a second sequence ofelectrical pulses to the electrode array sufficient to create a necroticzone when the second sequence of electrical pulses is delivered to thecentral electrode.

In certain embodiments, the volume of the necrotic zone may be greaterthan or equal to the volume of the thermal zone. FIG. 30 is a finiteelement model of an electrical field in tissue 501 of an electricalablation system according to certain embodiments. As shown in FIG. 30,the central electrode (524 a) may comprise an inner electrode and theplurality of the electrodes (524 b) may comprise outer electrodes. FIG.31 is a graphical representation of an electric field strength of about800 V/cm sufficient to induce irreversible electroporation at bodytemperature (about 37° C.). FIG. 32 is a graphical representation of anelectric field strength of about 200 V/cm sufficient to induceirreversible electroporation at an elevated temperature (about 55° C.).Without wishing to be bound to any particular theory, it is believedthat increasing the temperature of the tissue may reduce the electricfield necessary to cause cell necrosis in the undesirable tissue. Acomparison of FIGS. 31 and 32 shows that increasing the temperature ofthe tissue above body temperature (about 37° C.) reduced the electricfield necessary to cause cell necrosis in the tissue. Additionally, thevolume of the necrotic zone in FIG. 32 is greater than the volume of thenecrotic zone in FIG. 31. As shown in FIG. 31, the volume of thenecrotic zone in FIG. 31 does not contact each of the plurality ofelectrodes (524 b) of the electrode array. As shown in FIG. 32, thevolume of the necrotic zone in FIG. 32 contacts each of the plurality ofelectrodes and central electrode (524 b).

In certain embodiments, the system may comprise instructions to beexecuted by the processor to form a pre-heated zone by applying anelectric field that is less than about 800 V/cm by the first sequence ofelectrical pulses, and form a necrotic zone by applying an electricfield that is greater than about 800 V/cm by the second sequence ofelectrical pulses. The system may comprise instructions to form apre-heated zone by applying an electric field that is less than about700 V/cm by the first sequence of electrical pulses, and form a necroticzone by applying an electric filed that is equal to or greater thanabout 700 V/cm by the second sequence of electrical pulses. As discussedabove, the shape of the pre-heated zone may be dependent on the positionof the electrode array and ground pad. The pre-heated zone may besimilar to the thermal zone discussed above. The shape of the necroticzone may be dependent on the position of the central electrode andground pad. The size of the pre-heated zone may be less than or equal tothe size of the necrotic zone.

The shape and size of the thermal zone and/or necrotic zone may becontrolled by the configuration and/or position of the centralelectrode, electrode array, the geometry of the electrodes, e.g., thelength and width of each electrode, and the electrical pulses applied tothe electrodes, and/or ground pad. For example, the size and shape ofthe thermal zone and/or necrotic zone may be changed by retracting oradvancing the length of each electrode. In certain embodiments, thegeometry of the central electrode and/or each of the plurality ofelectrodes may be one of parallel and non-parallel. The centralelectrode and electrode array may be configured to induce thermalheating and/or induce cell necrosis in large masses of tissue of variousshapes and sizes by employing multiple electrodes.

In certain embodiments, the system may comprise instructions to beexecuted by the processor to heat the mass of tissue by applying anelectric field that is less than about 800V/cm by the first sequence ofelectrical pulses to lower the necrotic threshold, and induce cellnecrosis by irreversible electroporation by applying an electric filedthat is greater than about 800 V/cm by the second sequence of electricalpulses. In one embodiment, the system may comprise instructions to beexecuted by the processor to heat the mass of tissue by applying anelectric field that is less than about 700V/cm by the first sequence ofelectrical pulses to lower the necrotic threshold, and induce cellnecrosis by irreversible electroporation by applying an electric filedthat is greater than about 700 V/cm by the second sequence of electricalpulses.

In certain embodiments, the system may comprise instructions to beexecuted by the processor to apply a combination of a series of firstelectrical pulses having substantially lower voltage (in the range of1000 V to 2000 V) to the electrode array to induce thermal heating, anda series of second electrical pulses having a higher voltage to thecentral electrode to induce cell necrosis. In one embodiment, a firstseries of pulses may be applied to create thermal zone to increase thetemperature of the tissue and then a second series of pulses to inducecell necrosis at a lower voltage then otherwise would be necessarywithout the thermal heating of the tissue before inducing irreversibleelectroporation. In one embodiment, the system may comprise instructionsto apply a combination of a series of first electrical pulses havingsubstantially lower voltage to the electrode array to increase the sizeof the thermal zone at the same voltage.

In certain embodiments, the system may comprise instructions to beexecuted by the processor to apply a first sequence of electrical pulsesto the electrode array less than the necrotic threshold to lower thenecrotic threshold, and apply a second sequence of electrical pulses tothe central electrode to induce cell necrosis by irreversibleelectroporation. In one embodiment, the system may comprise instructionsto be executed by the processor to apply a first sequence of electricalpulses to the central electrode less than the necrotic threshold tolower the necrotic threshold when the first sequence of electricalpulses is applied to the electrode array. In one embodiment, the systemmay comprise instructions to be executed by the processor to not apply asecond sequence of electrical pulses to the electrode array to inducecell necrosis by irreversible electroporation when the second sequenceof electrical pulses is applied to the central electrode.

In certain embodiments, the system may comprise instructions to beexecuted by the processor to deliver a first energy dose that is lessthan the necrotic threshold to induce thermal heating by the firstsequence of electrical pulses, and deliver a second energy dose equal toor greater than the necrotic threshold to induce cell necrosis in thetissue by irreversible electroporation by the second sequence ofelectrical pulses. As discussed above, FIG. 7 is a graphicalrepresentation of a first sequence of electrical pulses that deliver afirst energy dose less than the necrotic threshold to induce thermalheating and a second sequence of electrical pulses that deliver a secondenergy dose to induce cell necrosis by irreversible electroporation. Inone embodiment, the system may comprise instructions to be executed bythe processor to deliver a first energy dose that is less than thenecrotic threshold to the central electrode to induce thermal heating bythe first sequence of electrical pulses. In one embodiment, the systemmay comprise instructions to be executed by the processor to not deliveran energy dose that is less than the necrotic threshold to the centralelectrode to induce thermal heating when the electrical pulses aredelivered to the electrode array.

In certain embodiments, the system may comprise at least one of atemperature sensor and a pressure sensor adjacent at least one of theelectrode array and central electrode. The temperature sensor maymeasure the temperature of the tissue surrounding one or more of theplurality of electrodes of the electrode array and/or central electrode.The pressure sensor may measure the pressure surrounding one or more ofthe plurality of electrodes of the electrode array and/or centralelectrode. In one embodiment, the apparatus may comprise at least one ofa temperature sensor and a pressure sensor adjacent at least one of theelectrode array and the central electrode. In one embodiment, thetemperature sensor and/or pressure sensor may be located within one ormore of the plurality of electrodes of the electrode array and/orcentral electrode. As discussed above, the pressure sensor may beadjacent to at least one of the vents in the shaft. In one embodiment,the pressure sensor may be adjacent at least one of the vents and thetemperature sensor may be located at the distal end of the flexibleshaft of the electrode array and/or central electrode. The energy sourcemay be operative to generate and deliver the second sequence ofelectrical pulses to the central electrode when at least one of apredetermined temperature and a predetermined pressure is achieved.

In certain embodiments, the system may comprise instructions to beexecuted by the processor to apply a sequence of electrical pulses tothe electrode array, the sequence of electrical pulses having amplitudesin the range of about ±100 VDC to about ±10,000 VDC, pulse widths in therange of about 1 μs to about 100 ms, and frequencies in the range ofabout 1 Hz to about 10,000 Hz, and re-apply the sequence of electricalpulses to the central electrode. In one embodiment, the energy sourcemay be configured to generate and deliver DC first pulses and the secondpulses at having amplitudes in the range of about ±100 VDC to about±3,000 VDC, pulse widths in the range of about 1 μs to about 100 ms, andfrequencies in the range of about 1 Hz to about 10,000 Hz. The sequenceof electrical pulses may comprise a series of pulse trains each having apulse train amplitude, a pulse train pulse width, and a pulse trainfrequency. The pulse trains may comprise a plurality of pulses eachhaving an amplitude, a pulse width, and a frequency. The first sequenceof electrical pulses may comprise a series of first pulse trains eachhaving a first pulse train amplitude, a first pulse train pulse width,and a first pulse train frequency, and the second sequence of electricalpulses may comprise a series of second pulse trains each comprising asecond pulse train amplitude, a second pulse train pulse width, and asecond pulse train frequency.

Referring to FIG. 33, according to certain embodiments, a method fordelivering energy to tissue having a necrotic threshold may generallycomprise inserting an electrode array comprising a plurality ofelectrodes into the tissue (step 602), inserting a central electrodeinto the tissue (step 604), positioning a ground pad proximal to thetissue (step 606), applying a first sequence of electrical pulses to theelectrode array less than the necrotic threshold to induce thermalheating in the tissue (step 608), applying a second sequence ofelectrical pulses to the central electrode equal to or greater than thenecrotic threshold to induce cell necrosis in the tissue by irreversibleelectroporation (step 610), and applying a ground potential to theground pad (step 612). The first sequence of electrical pulses may beapplied to electrode array and the central electrode. The secondsequence of electrical pulses may not be applied to the electrode array.

In certain embodiments, the method may comprise positioning each of theplurality of electrodes spaced apart from the other of the plurality ofelectrodes, and positioning the central electrode intermediate theplurality of electrodes. The user may position the electrode array andcentral array depending on the clinical conditions and/or clinicalapplication. The user may consider the number of electrodes and theposition of the electrodes relative to each other. The method maycomprise independently positioning each of the plurality of electrodesof the electrode array at a first position, depth, and angle in thetissue, and positioning the central electrode at a second position,depth, and angle in the tissue. The first position, depth, and/or anglemay be the same or different from the second position, depth, and/orangle. The method may comprise positioning one of the plurality ofelectrodes at the same or different position, depth, and/or angle of oneor more of the other plurality of electrodes. The method may comprisepositioning the plurality of electrodes spaced apart from the other ofthe plurality of electrodes. The method may comprise positioning thecentral electrode intermediate the plurality of electrodes. In oneembodiment, the method may comprise positioning each of the electrodesof the electrode array as an outer electrode and positioning the centralelectrode as an inner electrode.

In certain embodiments, the method may generally comprise coupling theelectrode array and the central electrode to an energy source operativeto generate the first sequence of electrical pulses and the secondsequence of electrical pulses. In various embodiments, the firstsequence of electrical pulses may be sufficient to create at least onethermal zone in a portion of the tissue induced by thermal heating in anarea near an electrode-tissue-interface of each of the plurality ofelectrodes, and the second sequence of electrical pulses may besufficient to create a necrotic zone in a portion of tissue induced byirreversible electroporation in an area surrounding each of theplurality of electrodes and the central electrode. The thermal zone ofone of the plurality of electrodes may contact the thermal zone of oneor more of the other of the plurality of electrodes. The thermal zone ofat least one of the plurality of electrodes may contact the centralelectrode. The thermal zone of each of the plurality of electrodes maycontact the central electrode. The thermal zone of each of the pluralityof electrodes may not contact the central electrode. The centralelectrode may be positioned within the thermal zone of each of theplurality of electrodes. The central electrode may be positioned outsidethe thermal zone of each of the plurality of electrodes. The volume ofthe necrotic zone may be greater than or equal to the volume of thethermal zone.

In certain embodiments, the method may generally comprise forming apre-heated zone by applying an electric field that is less than about800 V/cm by the first sequence of electrical pulses, and forming anecrotic zone by applying an electric filed that is greater than about800 V/cm by the second sequence of electrical pulses. The method maycomprise forming a pre-heated zone by applying an electric field that isless than about 700 V/cm by the first sequence of electrical pulses, andforming a necrotic zone by applying an electric filed that is greaterthan about 700 V/cm by the second sequence of electrical pulses. Theelectrode array and central electrode may be independently activated bythe generator. In certain embodiments, the volume and/or geometry of thethermal zone and/or necrotic zone may be tailored to the clinicalapplication. The relative positions and orientations of the electrodesmay enable different shapes and sizes of volumes of the pre-heated zoneand/or necrotic zone. The shape and size of the volume of pre-heatedzone and/or necrotic zone may be controlled by the configuration and/orposition of the electrode array and/or central electrode, the geometryof the electrodes, and parameters associated with the delivery of theelectrical pulse. The size of the pre-heated zone may be less than orequal to the size of the necrotic zone.

In certain embodiments, the method may generally comprise heating thetissue by applying an electric field that is less than about 800V/cm bythe first sequence of electrical pulses to lower the necrotic threshold,and inducing cell necrosis by irreversible electroporation by applyingan electric filed that is greater than about 800 V/cm by the secondsequence of electrical pulses. The method may comprise heating thetissue by applying an electric field that is less than about 700V/cm bythe first sequence of electrical pulses to lower the necrotic threshold,and inducing cell necrosis by irreversible electroporation by applyingan electric filed that is greater than about 700 V/cm by the secondsequence of electrical pulses.

In certain embodiments, the method may generally comprise applying afirst sequence of electrical pulses to the electrode array less than thenecrotic threshold to lower the necrotic threshold, and applying asecond sequence of electrical pulses to the central electrode to inducecell necrosis by irreversible electroporation. The method may compriseapplying the first sequence of electrical pulses to the centralelectrode when the first sequence of electrical pulses is applied to theelectrode array. The method may comprise applying the second sequence ofelectrical pulses to the electrode array when the second sequence ofelectrical pulses is applied to the central electrode. The method maycomprise not applying the second sequence of electrical pulses to theelectrode array when the second sequence of electrical pulses is appliedto the central electrode.

In certain embodiments, the method may generally comprise delivering afirst energy dose to the tissue that is less than the necrotic thresholdto induce thermal heating by the first sequence of electrical pulses,and delivering a second energy dose to the tissue equal to or greaterthan the necrotic threshold to induce cell necrosis in the tissue byirreversible electroporation by the second sequence of electricalpulses. The first energy dose may be delivered by the electrode arrayand/or central electrode. The first energy dose may not be delivered bythe central electrode. The second energy dose may be delivered by thecentral electrode. In one embodiment, the first energy dose may bedelivered by the electrode array and the second energy dose may bedelivered by the central electrode.

In certain embodiments, the method may generally comprise measuring atleast one of temperature and pressure adjacent at least one of theelectrode array and central electrode, applying a first sequence ofelectrical pulses to the electrode array to achieve at least one of apredetermined temperature and a predetermined pressure, and applying asecond sequence of electrical pulses to the central electrode when theat least one of a predetermined temperature and a predetermined pressureis achieved. The predetermined temperature may be body temperature,about 37° C., and greater than 37° C., such as, for example, 40° C. to60° C., 40° C. to 50° C., 40° C. to 55° C. and up to 60° C. Thetemperature of the tissue after the first sequence electrical pulses maybe greater that body temperature, such as, for example, 37° C. Thetemperature of the tissue after the first sequence of electrical pulsesmay be about 55° C. The first and second sequences of electrical pulsesmay be configured to maintain the tissue at a temperature between 50-60°C. The predetermined pressure may be atmospheric pressure.

In certain embodiments, the method may generally comprise applying asequence of electrical pulses to the electrode array, the sequence ofelectrical pulses having amplitudes in the range of about ±100 VDC toabout ±10,000 VDC, pulse widths in the range of about 1 μs to about 100ms, and frequencies in the range of about 1 Hz to about 10,000 Hz, andre-applying the sequence of electrical pulses to the central electrode.Each of the pulses may independently have amplitudes in the range ofabout ±100 VDC to about ±10,000 VDC, pulse widths in the range of about1 μs to about 100 ms, and frequencies in the range of about 1 Hz toabout 10,000 Hz. In one embodiment, the method may generally compriseapplying a sequence of electrical pulses having amplitudes in the rangeof about ±100 VDC to about ±3,000 VDC, pulse widths in the range ofabout 1 μs to about 100 ms, and frequencies in the range of about 1 Hzto about 10,000 Hz. The sequence of electrical pulses may comprise aseries of pulse trains each having a pulse train amplitude, a pulsetrain pulse width, and a pulse train frequency. The pulse trains maycomprise a plurality of pulses each having an amplitude, a pulse width,and a frequency. As discussed above, the first sequence of electricalpulses may comprise a series of first pulse trains each having a firstpulse train amplitude, a first pulse train pulse width, and a firstpulse train frequency, and the second sequence of electrical pulses maycomprise a series of second pulse trains each comprising a second pulsetrain amplitude, a second pulse train pulse width, and a second pulsetrain frequency.

In certain embodiments, the method may generally comprise lowering thenecrotic threshold by heating the tissue by applying an electric fieldthat is less than about 800 V/cm by the first sequence of electricalpulses. The method may comprise lowering the necrotic threshold by 30%by heating the tissue by applying an electric field that is less thanabout 800 V/cm. The method may comprise lowering the necrotic thresholdby heating the tissue by applying an electric field that is less thanabout 700 V/cm by the first sequence of electrical pulses.

Once positioned by the user, at least one of the plurality of electrodesin the electrode array may be energized to form a pre-heated zone havinga first shape in the tissue treatment region. The electrode array may beinserted into a tissue treatment region to create a plurality ofpre-heated zones having a plurality of shapes by retracting the at leastone of the plurality of electrodes in the electrode array, rotating atleast one of the plurality of electrodes in the electrode array to a newlocation, advancing or retracting at least one of the plurality ofelectrodes in the electrode array into the tissue treatment region,and/or energizing or de-energizing at least one of the plurality ofelectrodes in the electrode array. For example, the shape of thepre-heated zone may be dependent on the position of the plurality ofelectrodes in the electrode array. When the central electrode isenergized, a necrotic zone having a second shape may be formed in thetissue treatment region. This process may be repeated as often asnecessary to create any number of necrotic zones using the electricalablation apparatus.

Various parameters, such as, for example, pressure, temperature, andduration, may be altered or adjusted according to the type of tissue inthe tissue treatment region and the desired size of the pre-heated zoneand/or necrotic zone. The size of the pre-heated zone may be less thanor equal to the size of the necrotic zone. In one embodiment, theablation apparatus may increase the size of the necrotic zone relativeto a similar ablation apparatus comprising a first sequence ofelectrical pulses to induce cell necrosis in the tissue by irreversibleelectroporation. At anytime, the surgeon or clinician may reposition theelectrical ablation apparatus within the tissue treatment region andbegin the process anew.

According to certain embodiments, the method may comprise applying afirst sequence of electrical pulses to the electrode array to inducethermal heating and applying a second sequence of electrical pulses tothe central electrode to induce cell necrosis by irreversibleelectroporation, wherein the first and second sequences of electricalpulses create a ratio of thermal volume to non-thermal volume of 5 to 1.The thermal volume may comprise the volume of the pre-heated zone. Inone embodiment, at least one of the first sequence of electrical pulses,the second sequence of electrical pulses, and sequence interval may beconfigured to create a ratio of thermal volume to non-thermal volume of2 to 1. In one embodiment, at least one of the first sequence ofelectrical pulses, the second sequence of electrical pulses, andsequence interval may be configured to create a ratio of thermal zonevolume to necrotic zone volume of 1 to 1.

According to certain embodiments, the method may comprise measuring atleast one of temperature and pressure of the tissue treatment region.The method may comprise measuring at least one of temperature andpressure of the undesirable tissue. The method may comprise measuring atleast one of temperature and pressure adjacent at least one of theplurality of electrodes of the electrode array and the centralelectrode. The method may comprise measuring at least one of temperatureand pressure adjacent at least one of the plurality of electrodes of theelectrode array and the central electrode and applying a sequence ofelectrical pulses when at least one of a predetermined temperature and apredetermined pressure is achieved. The method may comprise measuring atleast one of temperature and pressure adjacent at least one of theplurality of electrodes of the electrode array and the central electrodeand stopping a sequence of electrical pulses when at least one of apredetermined temperature and a predetermined pressure is achieved. Themethod may comprise measuring at least one of temperature and pressureadjacent at least one of the plurality of electrodes of the electrodearray and the central electrode and applying a sequence of electricalpulses to achieve at least one of a predetermined temperature and apredetermined pressure.

In one embodiment, the electrical ablation system comprising anelectrode array and a central electrode may be used to deliver energy totissue, such as, for example, undesirable tissue located on the surfaceof the liver. In use, the electrical ablation device may be introducedinto or proximate the tissue treatment region through a port of atrocar. The trocar may be introduced into the patient via a smallincision formed in the skin. The endoscope may be introduced into thepatient trans-anally through the colon, trans-orally down the esophagusand through the stomach using translumenal techniques, or through asmall incision or keyhole formed through the patient's abdominal wall(e.g., the peritoneal wall). The endoscope may be employed to guide andlocate the distal end of the electrical ablation device into orproximate the undesirable tissue. Prior to introducing the flexibleshaft through the trocar, the sheath may be slid over the flexible shaftin a direction toward the distal end thereof to cover each of theelectrodes of the electrode array and central electrode until the distalend of the electrical ablation device reaches the undesirable tissue.

Once the electrical ablation device has been suitably introduced into orproximate the undesirable tissue, the sheath may be retracted to exposethe at least one of the plurality of electrodes of the electrode arrayand/or central electrode to deliver energy to the undesirable tissue. Todeliver the energy to the undesirable tissue, the operator initially maylocate the each of the electrodes of the electrode array at a firstposition and the central electrode at a second position using endoscopicvisualization and maintaining the undesirable tissue within the field ofview of the flexible endoscope. The first position may be near aperimeter edge of the undesirable tissue. Once the electrodes arelocated into or proximate the undesirable tissue, the electrode arraymay be energized with a first sequence of electrical pulses to deliver afirst energy dose that is less than the necrotic threshold to inducethermal heating in the tissue surrounding the electrode/tissueinterface. Once the temperature and/or pressure of the undesirabletissue achieves a predetermined threshold, the central electrode may beenergized with a second sequence of electrical pulses to deliver asecond energy dose equal to or greater than the necrotic threshold toinduce cell necrosis in the tissue by irreversible electroporation tocreate a necrotic zone. For example, once the electrode array andcentral electrode are located in the desired positions, the undesirabletissue may be exposed to an electric field generated by independentlyenergizing the electrodes with the energy source.

According to certain embodiments, an ablation apparatus for deliveringenergy to tissue having a necrotic threshold may generally comprise anelectrode array comprising a plurality of electrodes and a centralelectrode coupled to an energy source operative to generate and delivera first sequence of electrical pulses to the electrode array and asecond sequences of electrical pulses to the electrode array, whereinthe first sequence of electrical pulses delivers a first energy dose tothe tissue that is less than the necrotic threshold to induce thermalheating in the tissue and the second sequence of electrical pulsesdelivers a second energy dose to the tissue equal to or greater than thenecrotic threshold to induce cell necrosis in the tissue by irreversibleelectroporation. The ablation apparatus may comprise a ground pad. Theground pad may be positioned proximal to or adjacent the tissue. Theablation apparatus may comprise a controller, including any of thecontrollers discussed herein. The controller may be coupled to theenergy source and configured to control at least one parameterassociated with the delivery of the electrical pulses. In variousembodiments, each of the plurality of electrodes may comprise outerelectrodes spaced apart from the other of the plurality of electrodes,and the central electrode may comprise an inner electrode intermediatethe plurality of electrodes.

According to certain embodiments, an ablation apparatus may comprise anenergy source configured to generate and deliver DC first pulses and thesecond pulses at frequencies in the range of 1 Hz to 10,000 Hz,amplitudes in the range of ±100 VDC to ±3000 VDC, and pulse width in therange of about 1 μs to about 100 ms. The first sequence of electricalpulses may be sufficient to create a thermal zone in a first portion ofthe tissue induced by thermal heating in an area near anelectrode-tissue-interface of each of the plurality of electrodes, andthe second sequence of electrical pulses may be sufficient to create anecrotic zone in a second portion of tissue induced by irreversibleelectroporation in an area surrounding each of the plurality ofelectrodes and the central electrode.

According to certain embodiments, a method of treating tissue maygenerally comprise obtaining an ablation apparatus comprising a centralelectrode and an electrode array coupled to an energy source operativeto generate and deliver a first sequence of electrical pulses and asecond sequence of electrical pulses to tissue having a necroticthreshold, wherein the first sequence of electrical pulses deliver afirst energy dose that is less than the necrotic threshold to inducethermal heating in the tissue and the second sequence of electricalpulses deliver a second energy dose equal to or greater than thenecrotic threshold to induce cell necrosis in the tissue by irreversibleelectroporation, inserting the electrode array into a mass of tissuehaving a necrotic threshold, applying a first sequence of electricalpulses to the electrode array less than the necrotic threshold to inducethermal heating, applying a second sequence of electrical pulses to thecentral electrode to induce cell necrosis by irreversibleelectroporation, and applying a ground potential to a ground pad,wherein the ablation apparatus is operative to reduce the necroticthreshold of the tissue relative to a corresponding ablation apparatushaving an energy source configured to deliver a sequence of electricalpulses to induce cell necrosis by irreversible electroporation.

According to certain embodiments, a method of treating tissue maygenerally comprise inserting a central electrode and an electrode arraycomprising a plurality of electrodes into a mass of tissue having amembrane potential and a necrotic threshold, applying a first sequenceof electrical pulses to the electrode array less than the necroticthreshold to induce thermal heating, applying a second sequence ofelectrical pulses to the central electrode to induce cell necrosis byirreversible electroporation, and applying a ground potential to aground pad proximal to the tissue. In one embodiment, the method maycomprise re-applying the sequence of electrical pulses to the centralelectrode. In one embodiment, an energy source may be operative togenerate and deliver a sequence interval between the first sequence andsecond sequence. The first sequence of electrical pulses may comprise aseries of first pulse trains each having a first pulse train amplitude,a first pulse train pulse width, and a first pulse train frequency, andthe second sequence of electrical pulses may comprise a series of secondpulse trains each comprising a second pulse train amplitude, a secondpulse train pulse width, and a second pulse train frequency. The firstpulse trains may comprise a plurality of first pulses each having afirst amplitude, a first pulse width, and a first frequency, and each ofthe second pulse trains may comprise a plurality of second pulses eachhaving a second amplitude, a second pulse width, and a second frequency.Each of the first pulses and the second pulses may independently haveamplitudes in the range of about ±100 VDC to about ±10,000 VDC, pulsewidths in the range of about 1 μs to about 100 ms, and frequencies inthe range of about 1 Hz to about 10,000 Hz.

Although the various embodiments of the devices have been describedherein in connection with certain disclosed embodiments, manymodifications and variations to those embodiments may be implemented.For example, different types of end effectors may be employed. Also,where materials are disclosed for certain components, other materialsmay be used. The foregoing description and following claims are intendedto cover all such modification and variations.

Any patent, publication, or other disclosure material, in whole or inpart, that is said to be incorporated by reference herein isincorporated herein only to the extent that the incorporated materialsdoes not conflict with existing definitions, statements, or otherdisclosure material set forth in this disclosure. As such, and to theextent necessary, the disclosure as explicitly set forth hereinsupersedes any conflicting material incorporated herein by reference.Any material, or portion thereof, that is said to be incorporated byreference herein, but which conflicts with existing definitions,statements, or other disclosure material set forth herein will only beincorporated to the extent that no conflict arises between thatincorporated material and the existing disclosure material.

What is claimed is:
 1. A method for delivering energy to tissue having anecrotic threshold, the method comprising: inserting an electrode arraycomprising a plurality of electrodes into the tissue; inserting acentral electrode into the tissue; positioning a ground pad proximal tothe tissue; applying a first sequence of electrical pulses to theelectrode array less than the necrotic threshold to induce thermalheating in the tissue; applying a second sequence of electrical pulsesto the central electrode equal to or greater than the necrotic thresholdto induce cell necrosis in the tissue by irreversible electroporation;and applying a ground potential to the ground pad.
 2. The method ofclaim 1 comprising coupling the electrode array and the centralelectrode to an energy source operative to generate the first sequenceof electrical pulses and the second sequence of electrical pulses. 3.The method of claim 1 comprising positioning each of the plurality ofelectrodes spaced apart from the other of the plurality of electrodes,and positioning the central electrode intermediate the plurality ofelectrodes.
 4. The method of claim 1 comprising applying the firstsequence of electrical pulses to the central electrode.
 5. The method ofclaim 1, wherein the second sequence of electrical pulses is not appliedto the electrode array.
 6. The method of claim 1, wherein the firstsequence of electrical pulses is sufficient to create at least onethermal zone in a portion of the tissue induced by thermal heating in anarea near an electrode-tissue-interface of each of the plurality ofelectrodes, and wherein the second sequence of electrical pulses issufficient to create a necrotic zone in a portion of tissue induced byirreversible electroporation in an area surrounding each of theplurality of electrodes and the central electrode.
 7. The method ofclaim 6, wherein the thermal zone of each of the plurality of electrodescontacts the thermal zone of the other of the plurality of electrodes.8. The method of claim 6, wherein the thermal zone of at least one ofthe plurality of electrodes contacts the central electrode.
 9. Themethod of claim 6, wherein the thermal zone of each of the plurality ofelectrodes contacts the central electrode.
 10. The method of claim 6,wherein the central electrode is positioned within the thermal zone ofeach of the plurality of electrodes.
 11. The method of claim 6, whereinthe volume of the necrotic zone is greater than the volume of thethermal zone.
 12. The method of claim 6, wherein the thermal zone has avolume of about 4 cm³ to about 6 cm³.
 13. The method of claim 6, whereinthe thermal zone has a temperature greater than about 37° C.
 14. Themethod of claim 6, wherein the thermal zone has a temperature of aboutof 55° C.
 15. The method of claim 1 comprising: delivering a firstenergy dose to the tissue that is less than the necrotic threshold toinduce thermal heating by the first sequence of electrical pulses; anddelivering a second energy dose to the tissue equal to or greater thanthe necrotic threshold to induce cell necrosis in the tissue byirreversible electroporation by the second sequence of electricalpulses.
 16. The method of claim 1 comprising: forming a pre-heated zoneby applying an electric field that is less than about 800 V/cm by thefirst sequence of electrical pulses; and forming a necrotic zone byapplying an electric field that is greater than about 800 V/cm by thesecond sequence of electrical pulses.
 17. The method of claim 1comprising: heating a mass of tissue by applying an electric field thatis less than about 800V/cm by the first sequence of electrical pulses tolower the necrotic threshold; and inducing cell necrosis by irreversibleelectroporation by applying an electric field that is greater than about800 V/cm by the second sequence of electrical pulses.
 18. The method ofclaim 1 comprising: applying the first sequence of electrical pulses tothe electrode array less than the necrotic threshold to lower thenecrotic threshold; and applying the second sequence of electricalpulses to the central electrode to induce cell necrosis by irreversibleelectroporation.
 19. The method of claim 1 comprising: lowering thenecrotic threshold by heating the tissue by applying an electric fieldthat is less than about 800 V/cm by the first sequence of electricalpulses.
 20. The method of claim 1 comprising: measuring at least one oftemperature and pressure adjacent at least one of the electrode arrayand central electrode; applying the first sequence of electrical pulsesto the electrode array to achieve at least one of a predeterminedtemperature and a predetermined pressure; and applying the secondsequence of electrical pulses to the central electrode when the at leastone of the predetermined temperature and the predetermined pressure isachieved.
 21. The method of claim 1 comprising: applying a sequence ofelectrical pulses to the electrode array, the sequence of electricalpulses having amplitudes in the range of about ±100 VDC to about ±10,000VDC, pulse widths in the range of about 1 μs to about 100 ms, andfrequencies in the range of about 1 Hz to about 10,000 Hz; andre-applying the sequence of electrical pulses to the central electrode.22. A method for delivering energy to tissue having a necroticthreshold, the method comprising: inserting an electrode arraycomprising a plurality of electrodes into the tissue; inserting acentral electrode into the tissue; measuring at least one of temperatureand pressure in the tissue adjacent at least one of the electrode arrayand central electrode; applying a first sequence of electrical pulses tothe electrode array less than the necrotic threshold to induce thermalheating in the tissue until at least one of a predetermined temperatureand a predetermined pressure is achieved; and applying a second sequenceof electrical pulses to the central electrode equal to or greater thanthe necrotic threshold to induce cell necrosis in the tissue byirreversible electroporation when the at least one of the predeterminedtemperature and the predetermined pressure is achieved.
 23. A method fordelivering energy to tissue having a necrotic threshold, the methodcomprising: inserting an electrode array comprising a plurality ofelectrodes into the tissue; inserting a central electrode into thetissue; applying a first sequence of electrical pulses to the electrodearray less than the necrotic threshold to induce thermal heating andlower the necrotic threshold in the tissue; and applying a secondsequence of electrical pulses to the central electrode equal to orgreater than the necrotic threshold to induce cell necrosis in thetissue by irreversible electroporation.